CZ200259A3 - Preparation process of 2-(2-arylmorpholin-2-yl)ethanol derivatives and intermediates thereof - Google Patents

Abstract

The invention concerns novel methods for preparing enantiopure compounds of formula (I) wherein X represents a halogen atom, its additive salts with mineral or organic acids, or its salts with optically active organic acids. The invention also concerns intermediate compounds of formulae (II); (IV), (V), (VI), (VII), (XIII), (XIV), (XIX) and (XX). The invention further concerns enantiomerically pure compounds of formula (I), in the form of optically active salt with optically active organic acids.

Description

Preparation of 2- (2-arylmorpholin-2-yl) ethanol derivatives and their intermediates

Technical field

The present invention relates to a novel process for the preparation of substituted 2- (2-arylmorpholin-2-yl) ethanol derivatives in enantiomerically pure form and intermediates suitable for use in the process.

BACKGROUND OF THE INVENTION

Substituted 2- (2-arylmorpholin-2-yl) ethanol derivatives of formula I:

where X is a halogen atom and * represents the position of an asymmetric carbon atom, they are key intermediates in the preparation of tachykinin receptor antagonist compounds such as those described in International Patent Application WO 96/23787 and EP-A-776 893. For example, (R) - (+) 3- {1- [2- (4-Benzoyl-2- (3,4-difluorophenyl) morpholin-2-yl) ethyl] -4-phenylpiperidin-4-yl} 1,1-dimethylurea is described as being effective and a selective antagonist for human NK2 receptors of neurokinin A (X. Emonds-Alt et al., Neuropeptides, 1997, 31 (5), 449-458) and can therefore be used in particular in the treatment of respiratory, gastrointestinal, excretory, immune or cardiovascular diseases system and central nervous system and pain and migraine.

The term "halogen atom" means a bromine atom, a chlorine atom, a fluorine atom or an iodine atom.

. The subject of the present invention is preferably a novel process for the preparation of enantiomerically pure compounds of formula I wherein X is * a chlorine atom or a fluorine atom.

The preparation of the compounds of formula I is illustrated in International Patent Application WO 96/23787 and is carried out according to Scheme 1 below, wherein X is a halogen atom.

Scheme 1:

However, this method has disadvantages that do not allow its use on an industrial scale.

For example, a compound of formula I wherein X is a fluorine atom prepared by this process is obtained as described in International Patent Application WO 96/23787 in a very low yield, of the order of 1 to 2% relative to the starting benzaldehyde derivative.

• · · · · · • · · • »9 9 • 9 9 - · ·· • • · · 9 9 9 «· • • · t 9 • · • · ·

A compound of formula I wherein X is chlorine or fluorine can also be prepared by the enantioselective method described in Tetrahedron: Asymmetry, 1998, 9, 3251-3262. However, this process has the disadvantage that substances such as diketene and reagents such as dichlorobis (triphenylphosphine) palladium (II), AD-mix- ® or diethyl azodicarboxylate are used as starting materials, the cost of which prevents the production of the compound on an industrial scale.

We have now found a novel process for the preparation of an enantiomerically pure compound of formula I from simple starting materials and reagents in a yield of 5 to 25%.

SUMMARY OF THE INVENTION

Accordingly, in one aspect, the present invention provides a process for the preparation of a compound of formula I in enantiomerically pure form:

wherein X is a halogen atom, its salts with inorganic or organic acids, or its salts with optically active acids, wherein the method is characterized in that:

a) the compound of formula II in racemic form, in the form of a mixture of diastereoisomers or in enantiomerically pure form

(II): (IIa): R 1 = -CH ₂ , -n (IIb): R 1 = -COO-CH ₂ / w

• • · fc fcfcfcl (Ile): Rf = -COOCHCICH3 (IId): R 1 »-COO-C (CH3) ₃ (IIe): R =

CH.

wherein X is as defined for a compound of formula I and R 1 is a nitrogen protecting group selected from the group consisting of benzyl, benzyloxycarbonyl, 1chlorethyloxycarbonyl, tert-butyloxycarbonyl or α-methylbenzyl, is converted to a compound of formula III in racemic form, in the form of a mixture of diastereoisomers or in enantiomerically pure form:

(III): (II a): R _n =

O (IIIb): R 1 = -COO-CH ₂ (IIIe): R 1 = -COOCHCICH ₃ (IIId): R 1 = -COO-C (CH 3) 3

b) deprotecting the compound of formula III thus obtained;

c) if appropriate, when the compound of formula (I) thus prepared is obtained in racemic form, the enantiomers are separated and optionally the enantiomerically pure compound of formula (I) is converted into one of its salts with inorganic or organic acids.

• · · · · · · · · · · · · · · · · · · · · · ·

In Method A, preferably R 1 is benzyl or benzyloxycarbonyl.

When X is a chlorine atom, in process A preferably R 1 is a tert-butyloxycarbonyl group or a 1-chloroethyloxycarbonyl group.

When non-racemising reactions that retain chirality are used in steps a) and b) of process A of the present invention, the enantiomerically pure compound of formula I is prepared directly, using the enantiomerically pure compound of formula II as starting material.

In step a) of process A, the compound of formula II is converted to the compound of formula III by conventional methods known to those skilled in the art.

Preferably, in step a), compound II is first hydrogenated and then oxidized to give compound III.

The hydroboration reaction of the asymmetric alkene of formula II and then in situ oxidation of the resulting organoborane intermediate to give the primary alcohol of formula III is carried out according to conventional procedures, for example as described in J. Am. Chem. Soc., 1974, 96 (25), 7765-7770 or in J. Am. Chem. Soc., 1960; 82, 4708-4712.

Reagents known to those skilled in the art are used for hydroboration, for example either borane complexes such as borane-tetrahydrofuran complex or borane-dimethylsulfide complex or 9-borabicyclo [3.3.1] nonane or 9-BBN. The borane used can be generated in situ using conventional methods, for example, sodium borohydride or lithium borohydride and an acid such as Lewis acid.

···· · · ··· · · · · ·

Preferably, a borane-tetrahydrofuran complex, 9-borabicyclo [3.3.1] nonane or a borane generated in situ by reaction of trimethylsilyl chloride with sodium borohydride is used.

When a borane-tetrahydrofuran complex is used, it is present in the reaction mixture in a ratio of 0.3 to 1.5 molar equivalents per molar equivalent of the compound of formula II.

When 9-borabicyclo [3.3.1] nonane is used, it is present in the reaction mixture in a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula II.

When the borane is generated in situ by reacting trimethylsilyl chloride with sodium borohydride, both are used in a ratio of 3 to 5 molar equivalents per molar equivalent of the compound of formula (II).

The hydroboration reaction is carried out in an inert solvent such as an ether such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether such as an aromatic hydrocarbon such as toluene or xylene at a temperature between room temperature and the boiling point of the solvent for 5 to 48 hours.

The organoborane formed as an intermediate is then oxidized in a conventional manner. Preferably, the oxidation reaction is carried out under phase transfer catalysis by peroxide, in the presence of a strong base and a phase transfer catalyst in an inert solvent and water.

As peroxide, hydrogen peroxide is preferred. The hydrogen peroxide is used in a ratio of 3 to 5 molar equivalents per molar equivalent of the compound of formula II.

The base used during the reaction is selected from the group consisting of alkali metal hydroxides such as sodium hydroxide. In response ·· 4 ··· · · «··« ·

4 tt 999 9 9 999 * is used in a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula (II). .

The phase transfer catalyst is selected from substituted quaternary ammonium salts, such as tetrabutylammonium hydrogen sulfate. It is used in a ratio of 0.01 to 0.1 molar equivalent per molar equivalent of the compound of formula II.

The oxidation reaction is carried out in one of the solvents mentioned above for the hydroboration reaction and at a temperature of 0 to 60 ° C.

This oxidation reaction is highly exothermic and requires flow control during peroxide introduction and temperature control of the reaction medium.

The reaction is carried out for a period between the introduction of hydrogen peroxide and up to 48 hours.

Since the mixture of hydrogen peroxide and tetrahydrofuran is considered hazardous under industrial conditions, it is preferred to carry out the oxidation reaction in an aromatic solvent, preferably toluene. In this case, it may be necessary to change the solvent before the oxidation reaction or preferably before the hydroboration reaction.

In step b) of process A, protecting groups are removed from the compound of formula III thus obtained by conventional methods.

Thus, the removal of the benzyl group from compound IIIa, the removal of the benzyloxycarbonyl group from compound IIIb, or the removal of the α-methylbenzyl group from compound IIIa is carried out by hydrogenolysis, preferably by catalytic hydrogenation or by hydrogen transfer catalysis.

The catalytic hydrogenation is carried out in an inert solvent such as an alcohol (e.g. methanol, ethanol or propane-2ol), an aromatic hydrocarbon (e.g. toluene or xylene) or an ester (e.g. ethyl acetate) or in a mixture of the above solvents in the presence of a catalyst such as palladium on activated carbon or Raney nickel, at a pressure of 100 kPa to 1 MPa, at a temperature of 0 ° C to 100 ° C and for 1 to 24 hours.

Hydrogen transfer catalysis is carried out using ammonium formate in the presence of a catalyst such as palladium on activated carbon in an inert solvent such as an alcohol (e.g. methanol or ethanol) at a temperature between room temperature and the boiling point of the solvent for 2 to 48 hours.

Removal of the 1-chloroethyloxycarbonyl group from the compound of formula Hic is carried out by reaction with methanol at a temperature between room temperature and the boiling point of the solvent.

Removal of the tert-butyloxycarbonyl group from the compound of formula IIld is accomplished by acid hydrolysis with hydrochloric acid or trifluoroacetic acid, for example in an inert solvent such as an alcohol (e.g. methanol or ethanol), an ether (e.g. diethyl ether, dioxane or tetrahydrofuran) or halogenated hydrocarbon (e.g. dichloromethane) and at a temperature between -10 ° C and the boiling point of the solvent.

When the compound of formula I is obtained in racemic form, the enantiomers are separated in step c) by known methods. Preferably, the resolution is carried out by the preparation of an optically active salt by treatment with an optically active organic acid such as L - (+) - or D - (-) - mandelic acid, L - (-) - or D - (+) - di- para-tolyltartaric acid, L - (+) - or D - (-) - tartaric acid, L - (-) - or D - (+) dibenzoyltartaric acid or (1R) - (-) - or (1S) - ( +) - 10-camphorsulfonic acid and then resolution of the isomers by, for example, crystallization. The desired enantiomer is released from its salt in basic medium.

Preferably the resolution of the enantiomers of the compound of formula I is carried out by the preparation of an optically active salt, by treatment with L - (-) - or D (+) - di-para-tolyltartaric acid.

* 9 99 9 99 9 99

9 9 · · 99

9 9 9 9 9

9 9 9 9 9 9

9 9 99 999 99

The enantiomerically pure compounds of formula I in the form of optically active salts with optically active organic acids are novel and form part of the present invention.

Enantiomerically pure compounds of formula I in the form of optically active salts with optically active organic acids, wherein X is chlorine or fluorine are preferred.

Enantiomerically pure compounds of formula I in the form of salts with L - (-) - or D - (+) di-para-tolyltartaric acid are preferred.

The compounds of formula II in enantiomerically pure form, in racemic form or in the form of mixtures of diastereomers and their optional salts with inorganic acids or organic acids are novel and form part of the present invention.

Compounds of formula II wherein X is chlorine or fluorine are preferred.

Compounds of formula II wherein R 1 is benzyl or benzyloxycarbonyl are preferred.

In another aspect, the present invention provides process B for the preparation of compounds of formula II in enantiomerically pure form or in racemic form:

(II): (IIb): R 1 = -COO-CH ₂ (IIe): R 1 -COOCHCH 3 wherein X is halogen and R _x is benzyloxycarbonyl or 1-chloroethyloxycarbonyl, characterized in that the compound is of formula (IIa) in enantiomerically pure form or in racemic form:

(IIa) wherein X is as defined for the compound of formula (II), is reacted with benzyl chloroformate or 1-chloroethyl chloroformate in the presence of a base, with or without a solvent.

Preferably, in Method B, R 1 is a benzyloxycarbonyl group.

Benzyl chloroformate or 1-chloroethyl chloroformate are used in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula IIa.

The base used in the reaction is selected from organic bases such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or from alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate.

The base is used in the reaction at a rate of 0.01 to 1.5 molar equivalents per molar equivalent of the compound of formula IIa.

When the reaction is carried out in a solvent, the solvent is selected from aromatic hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene or dichlorobenzene, ethers such as tetrahydrofuran, dioxane or dimethoxyethane, esters such as ethyl acetate, amides such as N, N-dimethylformamide, nitriles such as acetonitrile or ketones such as acetone. The reaction is carried out at a temperature between -20 ° C to the boiling point of the solvent for 1 to 24 hours.

In another aspect, the present invention provides process C for the preparation of compounds of formula II in enantiomeric form in an enantiomeric manner. ...... * in pure form, in the form of mixtures of diastereoisomers or in racemic form:

wherein X is halogen and R _x is benzyl, tert-butyloxycarbonyl or α-methylbenzyl, its salts with inorganic or organic acids, characterized in that the compound of formula IV is in enantiomerically pure form, in the form of mixtures of diastereoisomers or in racemic form:

(iv)

HO (IVa) (IVd) (IVe)

wherein X and R 1 are as defined for Formula II, cyclize and optionally convert the Formula II thus obtained to a salt.

compound compound

In Method C, R 1 is preferably a benzyl group.

0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

The cyclization reaction of the diol of formula IV to the morpholine derivative of formula II can be carried out by known methods, for example as described in J. Med. Chem., 1994, 37, 2791-2796.

Preferably, the cyclization reaction is carried out under phase transfer catalysis conditions using an alkylsulfonyl or arylsulfonyl halide in the presence of a strong base and a phase transfer catalyst, in an inert solvent mixed with water.

Reaction of the primary alcohol of the compound of formula IV with an alkylsulfonyl or arylsulfonyl halide in the presence of a strong base allows first to form an alkylsulfonate or arylsulfonate ester which cyclizes in situ to form a morpholine ring under reaction conditions.

It has been found that when the cyclization reaction of an enantiomerically pure compound of formula IV is carried out under the above conditions, an enantiomerically pure compound of formula II is obtained whose asymmetric carbon atom has the same configuration.

Methanesulfonyl chloride, benzenesulfonyl chloride, or toluenesulfonyl chloride are preferably used as alkylsulfonyl or arylsulfonyl halides.

The alkylsulfonyl or arylsulfonyl halide participates in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula IV.

The base used in the reaction is selected from an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

The base participates in the reaction at a ratio of 5 to 10 molar equivalents per molar equivalent of the compound of formula IV.

The phase transfer catalyst is selected from substituted quaternary ammonium salts such as benzyltriethylammonium chloride.

♦ · · · · · · · ·

The catalyst participates in the reaction in a ratio of 0.01 to 0.1 molar equivalents per molar equivalent of the compound of formula IV.

The reaction is carried out in an inert solvent such as an aromatic hydrocarbon, for example toluene or xylene.

The reaction is carried out at a temperature between room temperature and 60 ° C for 1 to 24 hours.

The compound of formula IV in enantiomerically pure form, in the form of a mixture of diastereoisomers or in the form of a racemic mixture and its possible salts with inorganic or organic acids are novel and form part of the present invention.

A compound of formula IV wherein X is chlorine or fluorine is preferred.

A compound of formula IV wherein R 1 is benzyl is preferred.

In another aspect, the present invention provides process D for preparing a compound of formula IV in enantiomerically pure form

CH ₃ wherein X is a halogen atom and R _x is a benzyl or amethylbenzyl group, its salts with inorganic or organic acids, characterized in that:

(a) the compound of formula V in racemic form:

• · · ·· ·

(V) wherein X is as defined for the compound of formula IV and Hla is a halogen atom, reacts with benzylamine or R- (+) or S - (-) - α-methylbenzylamine in the presence of a base in an inert solvent to form a compound of formula VI in racemic form or in the form of a mixture of diastereoisomers:

b) separating the enantiomers or diastereoisomers of compound VI thus obtained;

c) reacting an enantiomerically pure compound of formula VI with:

either with ethylene oxide in the catalytic presence of an acid or in an inert solvent;

- or with a compound Hal '''', -CH ₂ -CH2-0-R ₂ (XXI) wherein R @ ₂ is an oxygen protecting group and Hal '''' is a halogen atom, in the presence of a base in an inert solvent, followed by removing an oxygen protecting group;

and optionally converting the enantiomerically pure compound of formula IV into a salt with an inorganic or organic acid.

In Method D, preferably R 1 is a benzyl group.

··········································

In step a) of method D, a compound of formula V wherein Hal is chlorine or bromine is preferably used.

In step a) of method D, compound V is first converted to an intermediate of the epoxide of formula VII:

which reacts with an amine under reaction conditions to form a compound of formula VI.

The amine participates in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula V.

The base used in the reaction is selected from alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate. Sodium bicarbonate is preferably used.

The base participates in the reaction at a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula V.

The inert solvent is selected from polar solvents such as acetonitrile, propionitrile or 1-methyl-2-pyrrolidone. The preferred solvent is propionitrile.

The reaction is carried out at a temperature of 80 to 120 ° C.

The reaction is carried out for 5 to 24 hours.

In step b) of process D, the enantiomers of the compound of formula VIa thus obtained are separated by conventional methods.

4 «·· ♦ · 4 4 4 44 4 • • 4 4 44 44 4 · 4 · ·· 444 444 • 4 4 44 44 · 44 4444

Preferably, the resolution is carried out by preparing an optically active salt by treatment with an optically active organic acid such as L (+) - or D - (-) - mandelic acid, L - (-) - or D - (+) - di-paratolyltartaric acid , L- (+) - or D - (-) - tartaric acid or L (-) - or D - (+) - dibenzoyltartaric acid and then separating the isomers by, for example, crystallization. The desired enantiomer is liberated from the salt in basic medium.

Preferably, resolution of the enantiomers of the compound of formula VIa is carried out by the preparation of an optically active salt by treatment with L - (+) - or D - (-) - mandelic acid.

In step b) of process D, the diastereoisomers of the compound of formula VIb thus obtained are separated by conventional methods. Preferably, the resolution can be carried out by preparing a salt with an inorganic or organic acid or an optically active organic acid, such as those mentioned above, and then separating the diastereoisomers, for example, by crystallization. The desired diastereoisomer may be liberated from the salt in a basic medium.

In step c), method D, the reaction of the enantiomerically pure compound of formula VI with ethylene oxide is carried out in a hydrogenator-type reactor because ethylene oxide is in gaseous form at the temperature used.

Ethylene oxide participates in the reaction at a ratio of 5 to 15 molar equivalents per equivalent of the compound of formula VI.

For example, the solvent may be an alcohol such as methanol.

The acid used in the reaction in a catalytic amount is selected from conventional inorganic or organic acids such as hydrochloric acid or acetic acid.

It has been found that the reaction between a compound of formula VI and ethylene oxide can be carried out without acid catalysis using an enantiomerically pure compound of formula VI in the form of a salt with an optic. With an active acid, preferably L - (+) - or D - (-) - mandelic acid. with acid as starting material.

The reaction is carried out at 0 to 60 ° C and for 2 to 24 hours.

According to another alternative of step c) of process D, the R ₂ protecting group is selected from conventional oxygen protecting groups known to those skilled in the art, such as tetrahydropyran-2-yl.

Preferably, a compound of formula XXI wherein Hal ^zzzz is chlorine or bromine is used.

The compound of formula XXI participates in the reaction at a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula VI.

The base used in the reaction is selected from alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate.

The base participates in the reaction at a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula VI.

The inert solvent is selected from polar solvents such as acetonitrile, propionitrile or 1-methyl-2-pyrrolidone.

The reaction is carried out at a temperature of 80 to 120 ° C and carried out for 5 to 24 hours.

Deprotection of the oxygen atom, R ₂ is carried out by methods known to those skilled in the art. For example, when R _{2 is a} tetrahydropyran-2-yl group, deprotection is accomplished by acid hydrolysis using an acid such as hydrochloric acid.

The reaction is carried out in an ethereal solvent such as diethyl ether or an alcohol such as methanol or in an aromatic solution such as toluene. at 0 ° C to the boiling point of the solvent and for 1 to 24 hours.

The compound of formula VI, in racemic form or in the form of a mixture of diastereoisomers or in enantiomerically pure form, and salts thereof with inorganic or organic acids or salts thereof with optically active acids are novel and form part of the present invention.

An enantiomerically pure compound of formula VIa in the form of a salt with L (+) - or D - (-) - mandelic acid is preferred.

Compound of Formula VI, where X is a chlorine atom or an atom chlorine, e advantageous. Compound formulas VI, where Ri is benzyl group is advantageous. Compound formulas XXI se prepared by protecting derivative 2-

halogenethanol using conventional procedures as described, for example, in Protective Groups in Organic Chemistry, J.F.W. McOmie, published by Plenum Press, 1973 and in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, edited by John Wiley and Sons, 1991.

In another aspect, the present invention provides a process E for the preparation of a compound of formula IV in racemic form or in the form of a mixture of diastereoisomers:

X

(IV) (IVa)

R = -COO-C (CH3) ₃

ch ₃

wherein X is a halogen atom and R 1 is a benzyl group or an α-methylbenzyl group, its possible salts with inorganic or organic acids, characterized in that:

(a) a compound of formula V in racemic form:

(V) wherein X is as defined for the compound of formula IV and Hal is a halogen atom, is reacted with either 2- (benzylamino) -1-ethanol or 2-amino-1-ethanol or with (R) - or (S) 2- (α-methylbenzylamino) -1-ethanol in the presence of a base and an inert solvent, and optionally converting the compound of formula IVa or IVe thus obtained into one of its salts with an inorganic or organic acid;

b) if appropriate, when the compound of formula V is used in step a) with 2-amino-1-ethanol, the obtained compound of formula IV'd:

(IVd) is reacted with di-tert-butyl dicarbonate in the presence of a base and an inert solvent to form a compound of formula IVd.

In Method E, R 1 is preferably a benzyl group.

·· ···················

Preferably, in step a) of process E, a compound of formula V wherein Hal is chlorine or bromine is used.

As in step a) of Method D, compound V is first converted to an intermediate of the epoxide of formula VII, which under reaction conditions reacts in situ with an aminoethanol derivative to give a compound of formula IVa, Ive or IV'd.

The aminoethanol derivative participates in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula V.

The base used in the reaction is selected from alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate. Sodium bicarbonate is preferably used.

The base participates in the reaction at a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula V.

The inert solvent is selected from polar solvents such as acetonitrile, propionitrile or 1-methyl-2-pyrrolidone. 1-Methyl-2-pyrrolidone is the preferred solvent.

The reaction is carried out at 80 to 120 ° C and for 10 to 24 hours.

If appropriate, in step b) of process E, the compound of formula IV'd is reacted with di-tert-butyl dicarbonate in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine in an inert solvent such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide and at a temperature of 0 ° C to 60 ° C.

(R) - or (S) -2- (α-Methylbenzylamino) -1-ethanol was prepared according to the procedure described in J. Am. Chem. Soc., 1984, 106, 747754.

• 4 · 4 4 4 4 4 4 4 4

44,444 444 4 4

444 444 444

4 44 444 44 4444

The compounds of formula V are novel and form part of the present invention.

A compound of formula V wherein X is chlorine or fluorine and Hal is chlorine or bromine is preferred.

In another aspect, the present invention provides a process F for preparing a compound of formula V:

wherein X is a halogen atom and Hal is a halogen atom, characterized in that:

(a) a compound of formula VIII:

(VIII) wherein X is as defined for the compound of formula V, is reacted with a compound of formula IX>

Hal'-CO-CH ₂ -Hal (IX) wherein Hal 'and Hal are a halogen atom, in the presence of a Lewis acid and an inert solvent, to give a compound of formula X:

(X)

b) reacting the compound of formula X thus obtained with a compound of formula

CH ₂ = CH-Mg-Hal (XI) wherein Hal is a halogen atom, in an inert solvent, followed by hydrolysis to give the expected compound of formula V.

According to a preferred aspect, the present invention relates to a process for the preparation of a compound of formula V wherein Hal is a chlorine atom or a bromine atom.

In step a), a compound of formula IX wherein Hal 'and Hal are both independently chlorine or bromine is preferably used and in step b) a compound of formula XI wherein Hal' 'is chlorine or bromine is used.

Step a) of Method F is a Friedel-Crafts reaction carried out under Perrier conditions using conventional procedures.

The Lewis acid is selected from conventional Lewis acids; preferably, ammonium chloride is used.

The Lewis acid is used in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of compound VIII.

Chloroacetyl chloride is preferably used as the haloacetyl halide of formula IX.

The compound of formula IX is used in a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula VIII.

· »· · · ·

The solvent is selected from aromatic hydrocarbons such as toluene or xylene, chlorinated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride, chlorobenzene or dichlorobenzene, or ethers such as tetrahydrofuran, dioxane or dimethoxyethane. Preferably dichloromethane is used.

The reaction is carried out at 0 to 100 ° C and for 1 to 24 hours.

Step b) of method F is a Grignard reaction which is carried out in a conventional manner.

The compound of formula XI is used in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula

X.

The solvent is selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. Tetrahydrofuran is preferably used.

The reaction is carried out at -20 to 0 ° C and for 1 to 24 hours.

After completion of the reaction, the reaction mixture is hydrolyzed according to conventional procedures by pouring it into, for example, a saturated aqueous ammonium chloride solution.

In another aspect, the present invention relates to a process G for the preparation of compound IVa in racemic form:

X

9 0 · 0 · 0 9 · 0 0 00

0 · · 0 0 0000

000 000 00 0

00,000 0 0 0 0 0,000,000,000

0 00 000 0 · 0009 where X is a halogen atom or a salt thereof with an inorganic or organic acid, characterized in that:

a) carrying out the preparation described in step a) of method F;

(b) reacting the compound of formula X thus obtained with a compound of formula XII:

r ₂ -o-ch, -ch ₂ -nh-ch ₂

(XII) wherein R ₂ is an oxygen protecting group, in the presence of a base in an inert solvent, to give a compound of formula XIII:

(XIII)

c) reacting the compound of formula XIII thus obtained with a compound of formula XI:

CH ₂ = CH-Mg-Hal (XI) where Hal is a halogen atom, followed by hydrolysis to give a compound of formula XIV:

(XIV)

d) deprotecting the compound of formula XIV and optionally converting the compound of formula IVa thus obtained into a salt with an inorganic or organic acid.

························································· I · ·· ····

Preferably, in step a), a compound of formula IX is used wherein Hal 'and Hal are each independently chlorine or bromine.

In step b) of process G, the protecting group R _{2 is} selected from conventional oxygen protecting groups known to those skilled in the art, such as tetrahydropyran-2-yl.

The compound of formula XII participates in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula

X.

The base is selected from alkali metal carbonates and bicarbonates, preferably sodium bicarbonate.

The base is used in a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula X.

The inert solvent is selected from inert solvents such as acetonitrile or propionitrile, or ethers such as tetrahydrofuran, halogenated solvents such as dichloromethane. Tetrahydrofuran is preferably used.

The reaction is carried out at a temperature between room temperature and the boiling point of the solvent for 1 to 24 hours.

Step c) of process G is a Grignard reaction which is carried out in a conventional manner.

Preferably, in step c), a compound of formula XI is used wherein Hal '' is a chlorine or bromine atom.

The compound of formula XI is used in the reaction at a ratio of 1.5 to 2 molar equivalents per molar equivalent of the compound of formula XIII.

The solvent is selected from ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane. Tetrahydrofuran is preferably used.

The reaction is carried out at a temperature between room temperature and the boiling point for 1 to 24 hours.

After completion of the reaction, the reaction mixture is hydrolyzed by pouring, for example, into a saturated ammonium chloride solution.

From the compound of formula XIV, the protecting group is removed in step d) of process G according to procedures known to those skilled in the art. For example, when R 2 is a tetrahydropyran-2-yl group, its removal is accomplished by hydrolysis with an acid such as hydrochloric acid. This can be generated in situ from acetyl chloride and methanol.

The reaction is carried out in an ether solvent such as diethyl ether or in an alcohol such as methanol at a temperature between 0 ° C to the boiling point of the solvent and for 1 to 24 hours.

The compound of formula XIII and its salts with inorganic or organic acids are novel and form part of the present invention.

A compound of formula XIII wherein X is chlorine or fluorine is preferred.

The compound of formula XIV and its salts with inorganic or organic acids are novel and form part of the present invention.

A compound of formula XIV wherein X is chlorine or fluorine is preferred.

The compound of formula XII is prepared by protecting 2- (benzylamino) -1-ethanol according to conventional procedures as described, for example, in Protective Groups in Organic Chemistry, J.F.W. McOmie, published by Plenum Press, 1973 and in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, edited by John Wiley and Sons, 1991.

In another aspect, the present invention provides an enantioselective process H for the preparation of a compound of formula IVa in enantiomerically pure form:

wherein X is a halogen atom, its salts with inorganic acids, characterized in that:

(a) compound of formula XI:

MgHar (XV) wherein X is the same as defined for the compound of formula IVa and Hal '' ^z is a halogen atom, is reacted with methyl- (R) - or (S) -2-phenylhexahydropyrrolo [1,2-c] imidazole -3-carboxylate of formula XVI:

(XVI) in the presence of magnesium chloride in an inert solvent, followed by hydrolysis to give the compound of formula XVII in enantiomerically pure form:

(XVII)

(b) reacting the compound of formula XVII thus obtained with a compound of formula XI:

CH ₂ = CH-Mg-Hal (XI) wherein Hal is a halogen atom, in an inert solvent, followed by hydrolysis to give the compound of formula XVIII in enantiomerically pure form:

(XVIII)

c) hydrolyzing the compound of formula XVIII thus obtained by treatment with an acid in an inert solvent as a mixture with water to give the compound of formula XIX in enantiomerically pure form:

(XIX)

d) the compound of formula XIX thus obtained is reacted with 2- (benzylamino) -1-ethanol in the presence of an acid in an inert solvent, then the imine salt formed as intermediate is read off with a reducing agent and optionally the enantiomer 4 9 9 4 4 • 4

44 * 4 4 ·

4

The 4444 pure compound of formula IVa is converted to one of its salts with inorganic or organic acids.

Preferably, in step a), a compound of formula XV wherein Hal " is chlorine or bromine is used, and in step b) a compound of formula XI wherein Hal " is chlorine or bromine is used.

Steps a), b) and c) of method H are carried out according to the method for asymmetric synthesis of α-hydroxyaldehydes described in T. Mukaiyama, Tetrahedron, 1981, 37 (23), 4111-4119.

In step d), the α-hydroxyaldehyde of formula XIX is reacted with 2- (benzylamino) -1-ethanol in the presence of an acid such as acetic acid in a polar solvent such as acetonitrile to form an imine intermediate which is chemically reduced using, for example sodium triacetoxyborohydride or sodium cyanoborohydride or catalytically using hydrogen and a catalyst such as palladium on activated carbon.

The enantiomerically pure or racemic compound of formula XIX is novel and forms part of the present invention.

A compound of formula XIX wherein X is chlorine or fluorine is preferred.

In another aspect, the present invention provides an enantioselective process I for the preparation of a compound of formula IVa in enantiomerically pure form:

X • 4 ·······

Where X is a halogen atom, its salts with inorganic or organic acids, characterized in that:

a) b) c) the preparation described in steps a), b) and c) of process H is carried out;

d) The thus obtained compound of formula XIX is reduced with a reducing agent in an inert solvent to give an enantiomerically pure compound of formula XX:

e) the compound of formula XX thus obtained is cyclized to give a compound of formula VII in enantiomerically pure form:

f) reacting the compound of formula VII thus obtained with 2 (benzylamino) -1-ethanol in the presence of an inert solvent and optionally converting the enantiomerically pure compound of formula IVa into one of the salts with an inorganic or organic acid.

In step d), the reduction of the aldehyde of formula XIX to the diol XX is carried out by conventional procedures using a reducing agent such as sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride. Sodium borohydride is preferably used.

The reaction is carried out in an inert solvent such as an aromatic solvent such as toluene, an alcohol such as ethanol, and an alcohol such as ethanol. Ether, for example tetrahydrofuran, or in mixtures of these solvents.

The reaction is carried out at a temperature between -70 ° C and the boiling point of the solvent and for 1 to 24 hours.

In step e), the cyclization of the diol of formula XX to the oxirane derivative of formula VII is preferably carried out under phase transfer catalysis conditions using an alkylsulfonyl or arylsulfonyl halide in the presence of a strong base and a phase transfer catalyst in an inert solvent as a mixture with water.

It has been found that when the cyclization reaction of an enantiomerically pure compound of formula XX is carried out under the above conditions, an enantiomerically pure compound of formula VII is obtained whose asymmetric carbon atom has the same configuration.

As alkylsulfonyl or arylsulfonyl halides, preference is given to methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride.

The alkylsulfonyl or arylsulfonyl halides participate in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula XX.

The base used in the reaction is selected from alkali metal hydroxides such as sodium hydroxide or potassium hydroxide.

The base participates in the reaction at a ratio of 5 to 10 molar equivalents per molar equivalent of the compound of formula XX.

The phase transfer catalyst is selected from substituted quaternary ammonium salts such as benzyltriethylammonium chloride.

The catalyst participates in the reaction in a ratio of 0.01 to 0.1 molar equivalents per molar equivalent of the compound of formula XX.

• Φ ΦΦΦΦ φ * * · φ φ φ φ φ φ φ φ 49 ΦΦΦΦ ΦΦΦ ΦΦ ΦΦΦΦ

The reaction is carried out in an inert solvent such as an aromatic hydrocarbon such as toluene or xylene, a chlorinated solvent such as dichloromethane.

The reaction is carried out at a temperature between room temperature to 60 ° C and for 1 to 24 hours.

In step f), the opening of the oxirane derivative of formula VII with 2- (benzylamino) -1-ethanol is carried out according to conventional procedures.

The amine participates in the reaction at a ratio of 1 to 1.5 molar equivalents per molar equivalent of the compound of formula VII.

The base is selected from alkali metal carbonates and bicarbonate such as sodium carbonate, potassium carbonate, and sodium bicarbonate.

The base participates in the reaction at a ratio of 1 to 2 molar equivalents per molar equivalent of the compound of formula VII.

The solvent is selected from polar solvents such as acetonitrile, propionitrile or 1-methyl-2-pyrrolidone.

The reaction is carried out at a temperature between room temperature and 120 ° C and for 1 to 48 hours.

It has been found that when the opening reaction of the enantiomerically pure compound of formula VII is carried out under the above conditions, a compound of formula IVa is obtained whose asymmetric carbon atom has the same configuration.

The enantiomerically pure or racemic compound of formula XX is novel and forms part of the present invention.

A compound of formula XX wherein X is chlorine or fluorine is preferred.

The enantiomerically pure or racemic compound of formula VII is novel and forms part of the present invention.

• · • ·

A compound of formula VII wherein X is chlorine or fluorine is preferred.

The compound of formula XVI used in step a) of method H or in step a) of method I is prepared from (S) - or (R) -proline according to the procedure described in Tetrahedron, 1981; 37 (23), 4111-4119, and as illustrated in the examples.

In any of the aforementioned methods A to I or in various steps of these methods, the compounds of formula I, IIa, IIb, IIc, IIc, IId, Ile, III, IVa, IVd, IVe, IVd, V, Via, Vle, VIII thus obtained can be obtained. X, XIII, XIV, XVII, XVIII, XIX and XX are subsequently isolated from the reaction mixture according to conventional procedures such as extraction, crystallization, distillation or chromatography. Further, the above compounds can either be isolated or used directly in another method or the next step in the medium in which they were prepared. Thus, each of Methods A to I or each of the steps of these methods may be combined to prepare a compound of Formula I.

If appropriate, the compounds of formula I, IIa, IIe, IIIa, IIIe, IVa, IVe, IV'd, VIa, VIIIe, XIII and XIV thus obtained can be isolated in free base or salt form by conventional procedures.

These salts include salts with inorganic or organic acids which allow the optional isolation or crystallization of a compound of formula I, IIa, Ile, IIIa, IIIa, IVa, IVe, IVd, Via, Vle, XIII and XIV and are, for example, hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, fumarate, succinate, naphthalene-2-sulfonate, glyconate, gluconate, citrate, isethionate, benzylsulfonate or para-toluenesulfonate.

When the compounds of formula I, IIa, Ile, IIIa, IIIa, IVa, IVe, IV'd, Via, V1e, XIII and XIV are obtained in the form of the free base, the salt preparation is carried out by reaction with the selected acid in an organic acid. ··· ··· ·· solvent. The corresponding salt is obtained by reacting the free base dissolved in, for example, an ether such as diethyl ether or an alcohol such as methanol, ethanol or propan-2-ol, or acetone or dichloromethane or ethyl acetate with a solution of the selected acid in one of of the aforementioned solvents, and the salt is isolated by conventional procedures.

For example, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, benzylsulfonate, para-toluenesulfonate, oxalate, maleate, succinate, fumarate or naphthalene-2-sulfonate are prepared.

Compounds of formula I, IIIa, IIIe, IIIa, IIIe, IVa, IVe, IV'd, VIa, V1e, XIII and XIV can be isolated in the form of one of their salts, for example the hydrochloride or oxalate; in this case, if necessary, the free base may be prepared by neutralizing said salt with an inorganic or organic base such as sodium hydroxide or triethylamine or an alkali metal carbonate or bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

According to a preferred aspect, the present invention provides processes A to I for the preparation of a compound of formula I, IIa, IIb, IIc, IId, Ile, IVa, IVd, IVe and V, wherein X is chlorine or fluorine.

In another preferred aspect, the present invention provides a compound of formula I in the form of an optically active salt with optically active organic acids, II, IV, V, VI, VII, XIII, XIX and XX, wherein X is chlorine or fluorine.

Accordingly, according to the present invention, the compounds of formula I are prepared using methods A to I above and using the following synthetic procedures defined and illustrated in the examples:

synthetic process I: method F, steps a and b; then method E, step a or step a and b; then Method C; then method A, steps a, bac.

synthetic process II: method F, steps a and b; then method D, steps a, b and c; then Method C; then method A, steps a, b.

synthetic process III: method G, steps a, b, c and d; then Method C; then method A, steps a, bac.

synthetic route IV: method H, steps a, b, c and d; then Method C; then method A, steps a and b.

synthetic process V: method I, steps a, b, c, d, e and f; then Method C; then method A, steps a and b.

synthetic procedures VI-X: as well as methods I-X

In this order, but between Method C and Method A, Method B is performed.

The invention will be further illustrated by the following non-limiting examples.

The following abbreviations are used in the examples below:

DCM: dichloromethane

THF: tetrahydrofuran

AT: room temperature.

Proton nuclear magnetic resonance ( ¹ H NMR) spectra were recorded at 200 MHz in perdeuterodimethylsulfoxide (d ₆ DMSO) using the d ₆ -DMSO peak as a standard. Chemical shifts δ are expressed as parts of millions (ppm). The observed signals are described as follows: s: singlet; d: doublet; dd: doublet of doublets; t: triplet; dt: triplet doublet; q: quadruplet; m: multiplet.

Enantiomeric purities were determined by chiral phase HPLC analysis of Chiracel OD or AD (cellulose-based stationary phase) and supercritical HPLC.

Example 1 - Synthetic Procedure I (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, L - (-) - di-para-tolyltartaric acid salt with acid (I): X = F

A) 2-Chloro-1- (3,4-difluorophenyl) ethanone; (X): X = F; Hal = Cl; method F, step a)

227.6 g of chloroacetyl chloride (IX: Hal = Hal '= Cl) are added under a nitrogen atmosphere to a suspension of 247.7 g of aluminum chloride in 450 ml of dichloromethane over 10 minutes and then the resulting yellow solution is heated to reflux. 200 g of 1,2-difluorobenzene (VIII: X = F) are then added dropwise over 2 hours and the reaction mixture is heated under reflux for 1 hour. After cooling the red mixture to 20 ° C, it is poured onto 1 kg of ice and allowed to stir for 30 minutes. After separation by settling, the organic phase is separated, the aqueous phase is extracted with 500 ml of dichloromethane, the combined organic phases are washed twice with 500 ml of water, 500 ml of saturated aqueous sodium bicarbonate solution and 500 ml of water, the organic phases are dried over magnesium sulphate and vacuum. 327.6 g of the expected product are obtained in the form of a tear-forming yellow oil.

Yield: 97.6% ^X H NMR: δ (ppm): 5.2: s: 2H; 7.6: dd: 1H; 7.8: u.c.: 1H; 8.0: dd: 1H.

B) 1-Chloro-2- (3,4-difluorophenyl) but-3-en-2-ol; (V) X = F; Hal = Cl; method F, step b) 0

800 ml of a 1Μ solution of vinylmagnesium bromide (XI: Hal = Br) in tetrahydrofuran was cooled to -10 ° C under nitrogen and a solution of 152.4 g of the compound obtained in the preceding step in 800 ml of tetrahydrofuran was added over 4.5 hours, The mixture was maintained at -10 ° C and then allowed to stir at -10 ° C for 20 minutes. The reaction mixture was hydrolyzed by pouring into 2 L of saturated aqueous ammonium chloride solution and allowed to stir for 30 minutes. After separation by settling, the organic phase is washed twice with 1 liter of saturated aqueous sodium chloride solution and then the organic phase is filtered to remove inorganic salts. A 1.5 liter solution of the expected compound in tetrahydrofuran is obtained, and this solution is used directly in the next step.

NMR: δ (ppm): 3.9: dd: 2H; 5.3: dd: 2H; 5.9: s: 1H; 6.2: u.c.: 1H; 7.3-7.5: u.c.: 3H.

C) 1- [Benzyl (2-hydroxyethyl) amino] -2- (3,4-difluorophenyl) but-3-en-2-ol (IVa): X - F. R 1 = -CH.

method E, step a)

A mixture of 67.2 g of sodium bicarbonate and 133 g of 2- (benzylamino) -1-ethanol in 500 ml of 1-methyl-2-pyrrolidinone is heated to 120 ° C and then a solution of the compound obtained in the reaction medium is added over 3 hours to distill tetrahydrofuran from the reaction medium. of the previous step (in 1.5 L of THF). After 1.5 liters of tetrahydrofuran were distilled off, the reaction mixture was allowed to stir at 120 ° C for 12 hours. After cooling to 20 ° C, the reaction mixture is poured into 2 liters of water, extracted with 2 liters of toluene and then the organic phase is washed twice with 500 ml of water. 2 L of water and 75 ml of concentrated hydrochloric acid solution were added to the organic phase. The acidified aqueous phase is washed with 500 ml of toluene, the aqueous phase is made alkaline by the addition of 96 ml of 10N sodium hydroxide solution and extracted with 1.2 liters of toluene and the organic phase is washed with 500 ml of water. . 1.23 kg of a toluene solution containing the expected compound are obtained and used directly in the next step.

The dry residue of 50 g of the solution contains 8.9 g of the expected compound, i.e., calculated on the whole solution, 219 g of the expected compound.

Yield: 82%, calculated relative to the starting compound of Step B of formula X: X = F; Hal = Cl.

@ ³ H NMR: .delta. (Ppm): 2.5: q: 2H; 2.9: s: 2H; 3.3: q: 2H; 3.6: dd: 2H; 4.5: t: 1H; 5.2: dd: 2H; 5.5: s: 1H; 6.3: dd: 1H; 7.1-7.5: u.c.: 8H.

(IIIa) C ₄ H ₄ O ₄ : X = F, R 1 = -CH;

D) 4-Benzyl-2- (3,4-difluorophenyl) -2-vinylmorpholine maleate Method C

The toluene solution of the compound obtained in the previous step is stirred at 760 rpm, 7.5 g of benzyltriethylammonium chloride are added, followed by a freshly prepared hot solution of 215.5 g of sodium hydroxide pellets in 215 ml of water, raising the temperature of the reaction mixture to 48 ° C. 139.23 g of benzenesulfonyl chloride are then added dropwise over 2 hours at a rate which allows the temperature of the reaction mixture to be maintained at 45 ° C. After cooling the reaction mixture to 20 ° C, it was hydrolyzed by adding 1 liter of water and allowed to stir for 1 hour. After separation by settling, the organic phase is washed twice with 1 liter of water (pH = 7) and dried over magnesium sulphate and the solvent is evaporated off under vacuum. 200 g of the expected compound are obtained in the form of the free base.

Yield: 96.5%.

A suspension of 94.7 g of maleic acid in 530 ml of ethyl acetate is heated to reflux for 10 minutes, and then a solution of 257.3 g of the free base compound (IIIa: X = F) in 116 ml of ethyl acetate is added. The reaction mixture was allowed to cool to room temperature and crystallization was initiated at 43 ° C by addition of 1 g of the maleate compound (IIIa: X-F) to induce rapid crystallization. The reaction mixture was cooled to 0 ° C and allowed to stir for 12 hours. The crystallization product is filtered off, washed three times with 100 ml of cold ethyl acetate and dried under vacuum at 30 ° C. 250 g of the expected compound are obtained in the form of the maleate.

Yield after salt preparation: 71%.

¹ H NMR: δ (ppm): 2.5: u.c.: 2H; 2.9: dd: 2H; 3.7: u.c.: 2H + 2H; 5.7: dt: 2H; 5.9: dd: 1H; 6.1: s: 2H; 7.1-7.6: u.c.: 8H.

E) 2- [4-Benzyl-2- (3,4-difluorophenyl) morpholin-2-yl] -1-ethanol (IIIa) · HCl: X = F, R, = -CH ₂ - / method A, step a 1 liter of a 0.5 M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran is charged to a reactor with a "control system (jacket oil temperature automatically controls the temperature of the reaction mixture) placed under a nitrogen atmosphere and at atmospheric pressure at body temperature. 500 DEG C. is distilled off with 500 ml of tetrahydrofuran. Solvent exchange is performed at a constant volume by introducing 500 ml of toluene, which takes 3 hours and the final temperature is 110 ° C. The mass was cooled to 20 ° C and precipitation of 9-borabicyclo [3.3.1] nonane dimer was observed. A solution of 131.4 g of the free base compound obtained in the previous step in 150 ml of toluene is then added over 25 minutes and the reaction mixture is allowed to stir for 12 hours. The reaction mixture was cooled to 5 ° C and stirred at 500 rpm and 50 mL of 10N sodium hydroxide solution was added, followed by 7 g of tetrabutylammonium hydrogen sulfate. The temperature of the reaction mixture is adjusted to 20 ° C and 60 g (53 ml) of a 11M solution of hydrogen peroxide in water (33%, 130 volumes, d = 1.13) are added at a mass flow rate 1 g / min. The temperature of the reaction mixture is adjusted to 35 ° C and 60 g of 11M hydrogen peroxide solution are added at a flow rate of 1.5 g / min. Finally, the temperature of the reaction mixture is adjusted to 50 ° C and 60 g of 11M hydrogen peroxide solution are added at a flow rate of 3 g / min. The reaction mixture was allowed to stir for 1 hour at 50 ° C. After separation by hot deposition, three phases are observed: toluene / cis-1,5-cyclooctanediol / water. After removal of the aqueous phase, the mixture is cooled to 20 ° C and the toluene phase is washed three times with 200 ml of water to remove the diol. The residual water is removed from the toluene phase by azeotropic treatment at constant volume with 200 ml of toluene. 1 g of the hydrochloride of the expected compound (IIIa: X = F) is then added to the clear toluene phase thus obtained, and 68 ml of a 6.1 M hydrogen chloride solution are then added dropwise over 40 minutes. The mixture was cooled to 20 ° C and allowed to stir for 3 hours and the resulting precipitate was filtered, washed three times with 100 ml toluene and dried under vacuum at 30 ° C. 124.3 g of the expected compound are obtained in the form of the hydrochloride.

Yield: 80.6%.

¹ H NMR: δ (ppm): 2.0: u.c.: 2H; 3.0: u.c.: 2H; 3.2: u.c.: 2H; 3.4: u.c.: 2H; 4.0: dd: 2H; 4.4: s: 2H; 7.1-7.8: u.c.: 8H.

F) 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, racemic (I): X = F, method A, step b) g 50% wet palladium on carbon is placed in of a hydrogenation reactor filled with nitrogen, then a solution of 236.3 g of the compound obtained in the previous step as the free base in 2.6 liters of methanol and 53 ml of concentrated hydrochloric acid solution is added. Hydrogenation is carried out at a hydrogen pressure of 300 kPa and at 40 ° C for 1 hour. The reaction mixture is cooled to 20 ° C and filtered through Whatman® filter paper, the filter paper is washed with 500 ml of methanol and the filtrate is evaporated under vacuum to a volume of 500 ml. . The solvent is exchanged with 500 ml of water, then 80 ml of 10N sodium hydroxide solution are added to the thus obtained aqueous solution and the mixture is allowed to stir for 1 hour at 15 ° C. The precipitate formed is filtered off, washed with 200 ml of water, taken up in 400 ml of diisopropyl ether and allowed to stir for 1 hour. The precipitate was filtered off, washed with 200 ml of diisopropyl ether and dried overnight in vacuo at 40 ° C. 120 g of the expected compound are obtained.

Yield: 78%.

G) (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, L - (-) - di-para-tolyltartaric acid salt (I) X = F; method A, step c)

A suspension of 60 g of the compound obtained in the preceding step in 780 ml of methanol is heated to 40 ° C. It is stirred at 240 rpm and a solution of 95.3 g of L - (-) - di-para-tolyltartaric acid in 300 ml of methanol is added dropwise over 50 minutes, maintaining the temperature of the mixture at 40 ° C. The reaction mixture was then allowed to stir for 10 minutes at 40 ° C and then for 1 hour at 35 ° C and cooled to 20 ° C over 2.5 hours. The mixture was allowed to stir for 12 hours at 20 ° C and the resulting precipitate was filtered, taken up in 150 ml of methanol and allowed to stir for 30 minutes. The precipitate is again filtered, washed with 60 ml of methanol and dried under vacuum at 40 ° C, washed with 60 ml of methanol and dried under vacuum at 40 ° C. 64.3 g of the expected compound are obtained in the form of a salt with L - (-) - di-paratolyltartaric acid.

Yield: 41.3%.

Final yield: 14.2%, calculated relative to the starting compound of Step A of formula VIII: X = F. Enantiomeric purity:

97.5% (e.e. = 95%).

Example 2 - Synthetic Procedure II (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol (I): X = F

A) 2-Chloro-1- (3,4-difluorophenyl) ethanone; (X): X = F; Hal = Cl; method F, step a)

The procedure is the same as that of Step A of Example 1.

B) 1-Chloro-2- (3,4-difluorophenyl) but-3-en-2-ol; (V): X = F; Hal = Cl; method F, step b)

560 ml of a 1.8 M solution of vinylmagnesium chloride (XI: Hal = Cl) in tetrahydrofuran was cooled to -15 ° C under nitrogen and a solution of 170 g of the compound obtained in the preceding step in 510 ml of tetrahydrofuran was added dropwise at -15 ° C over 2 hours. . The reaction mixture was hydrolyzed by pouring into 1 liter of saturated aqueous ammonium chloride solution and allowed to stir at room temperature for 1 hour. After separation by settling, the organic phase is washed twice with 1 liter of saturated aqueous sodium chloride solution. 840 ml of a solution of the expected compound in tetrahydrofuran are obtained and this solution is used directly in the next step.

C) 1- (Benzylamino) -2- (3,4-difluorophenyl) but-3-en-2-ol

method D, step a)

A mixture of 81 g of sodium bicarbonate and 112.7 g of benzylamine in 190 ml of tetrahydrofuran is heated to reflux and 300 ml of a solution of the compound obtained in the preceding step in tetrahydrofuran is quickly added. Once boiling was again reached, tetrahydrofuran was distilled off at a constant volume with the addition of the remaining solution of the compound from the previous step (540 mL). After the addition was complete, the reaction mixture was evaporated to a volume of 400 mL of tetrahydrofuran. Solvent exchange is performed at a constant volume with 580 ml of propionitrile, the temperature of the mixture at the end of the exchange being 85 ° C. The mixture was allowed to stir at 85 ° C for 8 hours. The propionitrile is then removed by constant volume solvent exchange by adding 1.1 L of toluene for 4.5 hours at the end of the exchange at 106 ° C. After cooling to room temperature, 1.3 L of toluene was added to give a 1.9 L final solution, and then the toluene phase was washed with 2 L of an aqueous solution containing 12.5 mL of acetic acid. 1.3 L of an aqueous solution containing 80 ml of concentrated hydrochloric acid is added to the organic phase, and the volume is made up by the addition of 400 ml of toluene and sufficient water to obtain 2.5 liters of the aqueous phase to dissolve the resulting oil. After extraction and separation by settling, the organic phase is washed with 500 ml of water and the aqueous phases are combined. The aqueous phases were made basic by the addition of 105 ml of 10N sodium hydroxide solution and extracted with 1.3 liters and then 0.7 liters of diisopropyl ether, the combined organic phases were washed three times with 2 liters of water and dried over magnesium sulphate and the solvent was evaporated in vacuo. 163 g of the expected product are obtained.

Yield: 64%, calculated from the starting material of Step B of formula X: X = F; Hal = Cl.

1 H NMR: δ (ppm): 3.2: dd: 2H; 4.1: s: 2H; 5.2-5.4: dd: 2H; 6.16.3: dd: 1H; 7.2-7.6: u.c.: 8H.

D) R - (+) - 1- (Benzylamino) -2- (3,4-difluorophenyl) but-3-en-2-ol, L - (+) - mandelic acid salt

method D, step b)

A suspension of 36.25 g of L - (+) - mandelic acid in 1.1 L of diisopropyl ether is heated to 60 ° C, a solution is added over 4 hours

4 45 4 9

«4

137.9 g of the compound prepared in the previous step in 555 ml of diisopropyl ether and then, at the end of the addition, the reaction medium is heated to 75 ° C for 1.5 hours to dissolve the resulting precipitate. The reaction mixture was cooled to 20 ° C at a rate of 0.3 ° C per minute and allowed to stir at 20 ° C for 8 hours. The precipitate formed is filtered off, suspended in 600 ml of diisopropyl ether, filtered again and dried under vacuum at 30 ° C. 103 g of the expected compound are obtained. The compound is taken up in 720 ml of ethyl acetate and heated to 60 ° C at a rate of 1 ° C per minute and the resulting solution is stirred at 60 ° C for 15 minutes. Cool to 0 ° C at 1 ° C per minute, start crystallization and allow the mixture to stir at 0 ° C for 4 hours. The precipitate formed is filtered off, washed with 150 ml of diisopropyl ether and dried under vacuum at 30 ° C. 60 g of the expected compound are obtained in the form of the salt with L - (+) - mandelic acid.

Yield: 28.5%.

Enantiomeric purity: 97.4% (e.e .: 94.8%).

[α] ²⁵ D = + 44.6 ° (c = 1, MeOH).

E) (R) - (+) - 1- [Benzyl (2-hydroxyethyl) amino] -2- (3,4-difluorophenyl) but-3-en-2-ol (IVa): χ = F, R, = - CH.

method D, step c)

A solution of 70.25 g of the compound obtained in the previous step in 200 ml of methanol is introduced into a Parr reactor, the reactor is placed under vacuum and the solution is cooled to 0 ° C. Ethylene oxide preheated to 30 ° C to 100 kPa is then introduced, and then the reaction medium is slowly warmed to 40 ° C and allowed to stir for 4 hours. After removal of the ethylene oxide and then purging the reaction medium with nitrogen, methanol was evaporated in vacuo. The remaining oil is taken up in 250 ml of water, the aqueous phase is acidified by adding 13 ml of concentrated hydrochloric acid, the acidified aqueous phase is washed twice with 250 ml of methyl tert-butyl ether and the aqueous phase is made alkaline by adding 18 ml of ION solution. sodium hydroxide and extracted twice with 250 ml of toluene. The combined organic phases are purified by chromatography on 500 g of silica gel, eluting five times with 250 ml of toluene / ethyl acetate (50/50; v / v). The phases were combined and the solvents were evaporated in vacuo. 43.5 g of the expected compound are obtained.

Yield: 81%.

^α D ²⁵ = + 13.9 ° (c = 1, MeOH)

(F) (R) - (+) - 4-Benzyl-2- (3,4-difluorophenyl) -2-vinylmorpholine (IIa) - HCl hydrochloride: X =

Method C

A solution of 40 g of the compound obtained in the preceding step in 200 ml of toluene is stirred at 760 rpm, 1.4 g of benzyltriethylammonium chloride and then a freshly prepared solution of 40 g of sodium hydroxide pellets in 40 ml of water are added, raising the temperature of the reaction medium to 48. Noc: 2 ° C. 25.43 g of benzenesulfonyl chloride are then added dropwise over 1 hour while the flow rate is adjusted to maintain the temperature of the reaction mixture at 45 ° C. After cooling the reaction mixture to 20 ° C, the mixture was hydrolyzed by adding 200 ml of water and allowed to stir for 1 hour. After separation by settling, the organic phase is washed twice with 200 ml of water (pH = 7) and dried over magnesium sulphate. 20 ml of a 6.1M solution of hydrogen chloride in ethanol are added dropwise to the thus obtained toluene solution, the mixture is stirred for 1 hour and the solvent is evaporated off under vacuum. The residue is taken up in 200 ml of toluene and stirred and the precipitate formed is filtered. The precipitate is washed with 100 ml of toluene and dried under vacuum at 30 ° C. 37 g of the expected compound are obtained in the form of the hydrochloride.

·· ····

·· ·· • * · ·

9 9

9 • 9

Yield: 87

Q.

o · α ²⁵ 0 = + 19.7 ⁰ (c = 1, MeOH)

G) R - (+) - 2- [4-Benzyl-2- (3,4-difluorophenyl) morpholin-2-yl] -1-ethanol (IIIa) -HCl hydrochloride: X = F; R1 = -CH method A, step a)

From 200 ml of a 0.5 M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran, 100 ml of tetrahydrofuran are distilled off in vacuo. The solvent is exchanged at constant volume with 100 ml of toluene and then the solution is cooled to 20 ° C (dimer 9-BBN precipitates). A solution of 30 g of the compound obtained in the previous step in 35 ml of toluene is added and the mixture is allowed to stir for 8 hours. 11 ml of 10N sodium hydroxide solution, then 1.6 g of tetrabutylammonium hydrogen sulphate in 2 ml of water are then added. The reaction mixture is stirred at 500 rpm and heated to 45 ° C, and 31 g of a 11M solution of hydrogen peroxide in water (33%, 130 volumes, d = 1.13) is added over 40 minutes at a rate to maintain the temperature of the reaction medium to 45 ° C and the reaction mixture was allowed to stir at 45 ° C for 15 minutes. After separation by settling, the alkaline aqueous phase is separated, 100 ml of water are added to dissolve the cis-1,5-cyclooctanediol as an oil, and the mixture is stirred and cooled to 20 ° C. After separation by settling, the organic phase is washed twice with 100 ml of water and the remaining water is removed from the organic phase by azeotropic distillation at constant volume until a clear phase is obtained. 16.4 ml of a 6.1M solution of hydrogen chloride in ethanol are then added dropwise and the mixture is left to stir for 1 hour at 20 ° C. The resulting precipitate was filtered off, washed three times with 20 ml of toluene and dried under vacuum at 40 ° C. 28 g of the expected product are obtained in the form of the hydrochloride

Yield: 90%.

· Fcfc · fc · fc · fcfc · fc fcfcfc α ²⁵ D = + 41.6 ° (c = 1, MeOH)

H) R - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol (I): X = F; method A, step b)

A solution of the compound prepared in the previous step in 300 ml of methanol is added under nitrogen to 3 g of 50% wet 10% palladium on carbon, then 30 ml of toluene are added. The hydrogenation is carried out at a pressure of 100 kPa at 30 ° C. The catalyst is filtered off through Whatman® filter paper, the filter paper is washed with methanol, and then the solvent filtrate is exchanged with 120 ml of water. After cooling, the aqueous phase is washed twice with 120 ml of methyl tert-butyl ether, the aqueous phase is made alkaline by the addition of 9 ml of 10N sodium hydroxide solution and the aqueous phase is allowed to stir for 1 hour in the cold. The precipitate obtained is filtered, washed with 100 ml of diisopropyl ether. vacuum at 40 ° C. 14 g of the expected compound are obtained.

Yield: 65%.

Final yield: 7.3%, calculated relative to the starting compound of Step A of formula VIII: X = F.

[α] ²⁵ D = + 21.9 ° (c = 1, MeOH).

Enantiomeric purity: 99 (e.e. = 98%).

Example 3 - Synthetic Procedure III (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, L - (-) - di-para-tolyltartaric acid salt with acid (I): X = F

A) a small N-benzyl-2- (tetrahydro-2H-pyran-2-yloxy) -1-ethylamine (XII) -C ₄ H ₄ O _4:

-Ό

Φ · ΦΦφ · · · · · · · · · · · · φ · φ · · ·

100 g of 2- (benzylamino) -1-ethanol are added at room temperature to a mixture of 110 g of benzenesulfonic acid in 1.8 liters of dichloromethane, the temperature being 34.4 ° C and pH = 2 after the addition is complete. 20 ° C and added dropwise with 105 ml of 3,4-dihydro-2H-pyran, the reaction mixture turns yellow, then rose and finally rinsed. The mixture was poured into 2 L of a 10% aqueous potassium carbonate solution, after separation by settling, the organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The oil obtained was dissolved in 200 ml of ethyl acetate, a hot solution of 72.7 g of maleic acid in 655 ml of ethyl acetate was added, and the mixture was allowed to stir overnight at room temperature. The resulting precipitate was filtered off, washed three times with 100 ml of ethyl acetate and dried in vacuo at room temperature. 207 g of the expected product are obtained in the form of the maleate.

Yield: 89%.

¹ H NMR: δ (ppm): 1.2-1.7: u.c.: 6H; 3.0: t: 2H; 3.1-3.8: u.c.: 2H;

4.1: s: 2H; 4.5: t: 1H; 7.2-7.4: u.c.: 5H; 8.0: s: 1H.

B) 2-Chloro-1- (3,4-difluorophenyl) ethanone;

(X): X = F; Hal = Cl; method G, step a).

The procedure is the same as in Step A of Example 1.

C) 2- {Benzyl [2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino} -1- (3,4-difluorophenyl) -1-ethanone (XHI): X = F; R ₂ = method G, step b) φφ φφ * *

1.5 l of a 10% aqueous potassium carbonate solution is added to a suspension of 200 g of the compound obtained in Step A in 1 l of dichloromethane, after separation by settling, the solvent is evaporated off under vacuum and the oil obtained is dissolved in 250 ml of tetrahydrofuran. This solution was added to a solution of 52.65 g of sodium bicarbonate in 10.35 ml of water and the reaction mixture was heated to reflux. A solution of 108.55 g of the compound obtained in Step B in 250 ml of tetrahydrofuran is then added dropwise over 50 minutes and the mixture is allowed to stir under reflux for 3 hours. The water was removed by azeotropic treatment under a nitrogen atmosphere while adding 600 mL of tetrahydrofuran for 2 hours. After cooling to room temperature, quadrupole molecular sieves were added to the solution and allowed to stir overnight. After filtration under nitrogen atmosphere, 800 ml of a solution of the expected compound in tetrahydrofuran is obtained, which is used directly in the next step.

¹ H NMR: δ (ppm): 1.4: u.c.: 6H; 2.7: dt: 1H; 3.3: u.c.: 2H; 3.6: u.c.: 2H; 3.7: s: 2H; 4.0: s: 2H; 4.4: u.c.: 2H; 7.0-7.4: u.c.: 8H.

D) 1- {Benzyl [2- (tetrahydropyran-2-yloxy) ethyl] amino} -2- (3,4-difluorophenyl) but-3-en-2-ol (XIV): X = F; R.

method G, step c)

A solution of the compound obtained in the preceding step in tetrahydrofuran was added to 911 ml of a 1M solution of vinylmagnesium bromide (XI: Hal = Br) in tetrahydrofuran over 30 minutes under a nitrogen atmosphere at a flow rate of 55 ° C and then allowed to stir for two hours. hours at 50 ° C. The reaction mixture was hydrolyzed by pouring into 1.5 L of saturated ammonium chloride solution over 45 minutes while maintaining the temperature of the reaction mixture at 30 ° C. Add 500 ml of water. After separation by settling, the aqueous phase is extracted with 1 liter of diisopropyl ether, the organic phases are combined and the solvent is evaporated off under vacuum.

241 g of the expected compound are obtained, which product is used as is in the following stage.

E) 1- [Benzyl (2-hydroxyethyl) amino] -2- (3,4-difluorophenyl) but-3-en-2-ol (IVa): X = F, R ₁ = -CH

method G, step d)

500 ml of methanol are cooled to 5 ° C and 57 ml of acetyl chloride are added dropwise at 10 ° C. this solution was then added over 1 hour at room temperature to a solution of 241 g of the compound obtained in the previous step in 500 ml of methanol and the reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture is evaporated in vacuo, the oily residue is dissolved in 1 liter of water, the aqueous phase is washed twice with 500 ml of diisopropyl ether and the aqueous phase is made alkaline by addition of 40 g of sodium hydroxide pellets and extracted twice with 800 ml of toluene. 500 ml of water and 400 ml of toluene are added to the organic phase and the phases are separated by settling. 2.083 l of a solution of the expected compound are obtained, which is used directly in the next step (HPLC content: 91 mg / ml, i.e. 189.5 g of IVa: X-F).

F) 4-Benzyl-2- (3,4-difluorophenyl) -2-vinylmorpholine maleate (IIa) * C4H4O4:

Method C

6.4 g of benzyltriethylammonium chloride was added to a toluene solution of the compound prepared in the previous step, and then a freshly prepared and hot solution of 187 g of sodium hydroxide pellets in 187 ml of water was added while maintaining the temperature of the reaction mixture at 50 ° C. 86 ml of benzenesulfonyl chloride are added dropwise over a period of 2 hours at a flow rate which allows the temperature of the reaction mixture to be maintained at a maximum of 55 ° C. After cooling to room temperature, the reaction mixture was cooled to room temperature

1 liter of water was added and the mixture was allowed to stir for 15 minutes. After separation by standing, the organic phase is washed twice with 1 liter of water and 1 liter of saturated aqueous sodium chloride solution. The organic phase is purified by chromatography on 180 g of silica gel and then washed with 400 ml of toluene. The toluene phases were combined and the solvent was evaporated in vacuo. 137.8 g of the expected compound are obtained in the form of the free base.

A suspension of 50.7 g of maleic acid in 284 ml of ethyl acetate is heated to boiling, then a solution of 137.8 g of the free base compound prepared above in 62 ml of ethyl acetate is added and the mixture is allowed to stir for 12 hours until the temperature is lowered to room temperature. . The mixture was cooled to 0 ° C and allowed to stir for 1 hour and the resulting precipitate was filtered off, washed four times with 50 ml cold ethyl acetate and dried under vacuum at room temperature. 157 g of the expected compound are obtained in the form of the maleate.

Yield: 60% calculated relative to the starting compound of step C) of formula X: X = F; Hal = Cl.

G) 2- [4-Benzyl-2- (3,4-difluorophenyl) morpholin-2-yl] -1-ethanol (IIIa) -HCl: X = F; R1 = -CH.

method A, step a)

500 ml of water are added to a suspension of 245.3 g of the compound obtained in the preceding step in 500 ml of toluene and then 120 ml of 10N sodium hydroxide solution. After separation by settling, the aqueous phase is extracted with 500 ml of toluene, the organic phases are combined and the water is removed by constant azeotropic distillation with the addition of toluene. The toluene solution was evaporated to a volume of 350 ml.

800 ml of a 0.5 M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran is introduced into a reactor with an "atmosphere control system"

4 * 4 <

· 4 4

4 4 4 4 4 •• 4> 4 ·· · 44

44 • 4 4 ·

4 4

4 4

4 4

4444 of nitrogen and the solution was evaporated at atmospheric pressure to a volume of 400 ml. Again, 600 mL of a 0.5 M solution of 9-BBN in tetrahydrofuran was added and the solution was evaporated to a volume of 700 mL of tetrahydrofuran. Solvent exchange is carried out at constant volume by introducing 700 ml of toluene while the temperature of the mixture during the addition is 68 to 110 ° C. The mass was cooled to 20 ° C and precipitation of dimeric 9-BBN was observed. 350 ml of the solution of compound IIIa: X = F prepared above are then added and the mixture is left stirring for 8 hours. The reaction mixture was cooled to 5 ° C and 9.6 g of tetrabutylammonium hydrogen sulfate and then 69 ml of 10N sodium hydroxide solution were added. The temperature of the reaction mixture is adjusted to 20 ° C and 72.3 g of a 11M solution of hydrogen peroxide in water (33%, 130 volumes, d = 1.13) are added at a flow rate of 1.2 g per minute. The temperature of the reaction mixture is adjusted to 35 ° C and 72.3 g of a 11M solution of hydrogen peroxide in water (33%, 130 volumes, d = 1.13) are added at a flow rate of 1.8 g per minute. Finally, the temperature of the reaction mixture is adjusted to 50 ° C and 72.3 g of a 11M solution of hydrogen peroxide in water (33%, 130 volumes, d = 1.13) are added at a flow rate of 3 g per minute. The mixture was allowed to stir at 50 ° C for 1 hour, separated by hot settling, observing 3 phases: toluene / cis-1,5-cyclooctanediol / water. The aqueous phase is separated, the toluene phase is washed twice with 200 ml of water to remove the diol, then the organic phase is cooled to 20 ° C and dried over sodium sulfate. 95 ml of a 6.1M solution of hydrogen chloride in ethanol are added to the organic phase, crystallization is initiated by the addition of 1 g of hydrochloride of compound IIIa: X = F) and the mixture is allowed to stir for 3 hours at room temperature. The precipitate formed is filtered off, washed three times with 250 ml of toluene and dried under vacuum at room temperature. 164 g of the expected compound are obtained in the form of the hydrochloride.

Yield: 86%.

H) 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, racemic

(I): X = F; method A, step b) g 50% wet 10% palladium on carbon was placed in a hydrogenation reactor placed under a nitrogen atmosphere and then a solution of 164 g of the compound obtained in the previous step as hydrochloride in 1.6 liters of sodium hydroxide was carefully added. The mixture was hydrogenated at 40 kPa at 40 ° C for 3 hours. After cooling to room temperature, the catalyst was filtered through Whatman® filter paper, the filter paper was washed with 100 ml of methanol, 55 ml of 10N sodium hydroxide solution were added to the filtrate, and the methanol was evaporated in vacuo to a volume of 200 ml. The solvent is exchanged with water by azeotropic treatment. After removal of all methanol, the mixture was allowed to stir for 1 hour and the resulting precipitate was filtered off, washed twice with 100 ml of water and dried under vacuum overnight at 40 ° C. 102 g of the expected compound are obtained.

Yield: 94.8%.

(I) (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, L - (-) - di-para-tolyltartaric acid salt (I) X = F; method A, step c)

A suspension of 95 g of the compound obtained in the preceding step in 1.235 liters of methanol is heated to 40 ° C and a solution of 150.88 g of L - (-) - dipara-tolyltartaric acid in 475 ml of methanol is added over 1 hour. When half of this solution was added, crystallization was started by adding 0.4 g of the cleaved salt, and when the addition was complete, the mixture was allowed to stir for 4.5 hours while cooling to room temperature. The mixture is cooled to 20 ° C and stirring is continued for 2 hours and the resulting precipitate is filtered off, washed twice with 100 ml of ethanol and dried under vacuum at room temperature. 100 g of the expected compound are obtained in the form of a salt with L (-) - di-paratolyltartaric acid.

Yield: 40.8%.

······ · · · · ·

Final yield: 19.5%, calculated relative to the starting compound of step B) of formula VIII: X = F.

Enantiomeric purity: 97.4% (e.e. = 94.8%).

Example 4 - Synthetic Procedure IV (S) - (-) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol (I): X = F

A) Methyl 2-phenylhexahydro-1H-pyrrolo [1,2-c] imidazole-3-carboxylate, one isomer XVI

a) (S) -1 - [(Benzyloxy) carbonyl] proline

This compound is commercially available.

b) Benzyl (S) -2- (anilinocarbonyl) -1-pyrrolidinecarboxylate

9.7 ml of N-methylmorpholine are added under a nitrogen atmosphere to a solution of 20 g of the compound prepared in the previous step in 200 ml of acetonitrile, this solution is cooled to 0 ° C and 7.7 ml of ethyl chloroformate are added over 45 minutes. The reaction mixture was cooled to 0 ° C and 7.3 mL of aniline was added over 45 minutes. The reaction mixture is evaporated in vacuo, the oily residue is extracted with 200 ml of ethyl acetate, the organic phase is washed twice with 200 ml of pH 2 buffer, 200 ml of water and twice with 200 ml of 10% aqueous sodium bicarbonate solution, 200 ml of ethyl acetate. over sodium sulfate and filtered, and the solvent was evaporated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether and the mixture is allowed to stir for 1 hour and the resulting precipitate is filtered off, washed with 20 ml of tert-butyl methyl ether and dried at 40 ° C. 20.8 g of the expected product are obtained.

Yield: 80%.

¹ H NMR: δ (ppm): 1.8: u.c.: 2H; 2.2: u.c.: 2H; 3.5: u.c.: 2H; 4.3 ^ dt:

1H; 4.9: d: 1H; 5.1: d: 1H; 7.0-7.4: u.c.: 8H; 8.6: u.c.: 2H; 10: d:

1H.

c) (S) -N-Phenyl-2-pyrrolidinecarboxamide

A solution of 20 g of the compound obtained in the preceding step and 5.3 ml of concentrated hydrogen chloride in 300 ml of ethanol is carefully poured under nitrogen atmosphere to 2 g of 50% wet 10% palladium on carbon and hydrogenation is carried out for 2 hours at atmospheric pressure and room temperature. . Add 5 ml of concentrated hydrochloric acid; the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is dissolved in 200 ml of water, the aqueous phase is washed with 200 ml of ethyl acetate, the aqueous phase is made alkaline by the addition of 5 g of sodium hydroxide pellets and extracted three times with 200 ml of dichloromethane. The dichloromethane was removed by azeotropic treatment with tetrahydrofuran and then the tetrahydrofuran was evaporated in vacuo. 11.5 g of the expected product are obtained.

Yield: 94.5%.

NMR: .delta. (Ppm): 1.7: u.c.: 2H; 2.0: u.c.: 2H; 2.9: t: 2H; 3.3: s: 1H; 3.7: u.c.: 1H; 7.1: dd: 1H; 7.3: dd: 1H; 7.7: d: 2H; 9.9: s: 1H.

d) (S) -N- (2-Pyrrolidinylmethyl) aniline. A 1M solution of lithium aluminum hydride in tetrahydrofuran was heated to reflux under a nitrogen atmosphere and a solution of 12 g of the compound obtained in the previous step in 120 ml tetrahydrofuran was slowly added. After allowing to warm to room temperature, 3 ml of water, 3 ml of 10N sodium hydroxide solution and 9 ml of water are carefully added and the mixture is allowed to stir overnight at room temperature. The mixture was filtered and the filtrate was evaporated in vacuo. The oil obtained is distilled under vacuum (b.p. = 158-164 ° C / 0.1 mbar). 8.6 g of the expected product are obtained.

Yield: 76%.

¹ H NMR: δ (ppm): 1.1: u.c.: 2H; 1.6: u.c.: 2H; 2.6-2.8: u.c.: 4H; 3.1:

m: 1H; 5.3: t: 1H; 6.4: u.c.: 3H; 7.0: u.c.: 2H.

e) Methyl 2-phenylhexahydro-1H-pyrrolo [1,2-c] imidazole-3-carboxylate, one isomer

1.89 g of methyl hydroxymethoxyacetate is added to a solution of 2.64 g of the compound obtained in the preceding step in 25 ml of toluene, and then the mixture is refluxed for 1.5 hours under azeotropic removal of water. The reaction mixture is allowed to cool to room temperature, 25 ml of water are added to dissolve the insoluble matter, the organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. 3.67 g of the expected product are obtained.

Yield: quantitative 1 H NMR: δ (ppm): 1.4-2.0: u.c.: 4H; 2.6: u.c.: 1H; 3.1: u.c.: 2H; 3.5: u.c.: 1H; 3.6: s: 3H; 3.8: u.c.: 1H; 4.8: s: 1H; 6.4: dd: 2H; 6.6: dd: 1H; 7.1: dd: 2H.

B) (3,4-Difluorophenyl) (2-phenylhexahydro-1H-pyrrolo [1,2-c] imidazol-3-yl) methanone, one isomer (XVII): X = F; method H, step a)

A solution of 3,4-difluorophenylmagnesium bromide (XV: X = F; Hal '' = Br) is prepared from 0.85 g of magnesium sawdust, 4 g of 1-bromo-3,4-difluorobenzene and 20 ml of tetrahydrofuran and this solution is stored at temperature rooms.

Next, 0.13 ml of 1,2-dichloroethane was added to a mixture of 0.4 g of magnesium sawdust in 20 ml of tetrahydrofuran under a nitrogen atmosphere and the mixture was heated until it became cloudy and the ethylene oxide gas was removed. 1,17 ml of 1,2-dichloroethane are added in 0.13 ml portions and refluxed for 1 hour. This gives a channel of anhydrous magnesium chloride suspension of 9,999,999,999,999,999,999,999,999,999,999 channels After cooling to room temperature, a solution of 3.67 g of the compound obtained in Step A) in 37 ml of tetrahydrofuran is added and the mixture is refluxed for 1 hour and allowed to cool to room temperature. This solution was then cooled to -70 ° C, 20.4 ml of the 3,4-difluorophenylmagnesium bromide solution prepared above was added at this temperature, and the mixture was allowed to stir at -70 ° C for 1 hour. The reaction mixture was poured into 30 mL of saturated aqueous ammonium chloride solution and allowed to stir for 15 minutes. The tetrahydrofuran is evaporated under reduced pressure, the residue is taken up in 50 ml of diisopropyl ether, the organic phase is washed with 30 ml of water and 30 ml of saturated aqueous ammonium chloride solution and dried over magnesium sulphate and the solvent is evaporated off under vacuum. 4.59 g of the expected product is obtained.

Yield: 85%.

C) 1- (3,4-Difluorophenyl) -1- (2-phenylhexahydro-1H-pyrrolo [1,2-c] imidazol-3-yl) -2-propan-1-ol, one isomer (XVIII): X = F; method H, step b)

A solution of 4.59 g of the compound prepared in the previous step in 30 ml of tetrahydrofuran is cooled to -70 ° C, 28 ml of a 1M solution of vinylmagnesium bromide (XI: Hal = Br) in tetrahydrofuran is slowly added at -70 ° C and the mixture is allowed to stir. hour at -70 ° C. The reaction mixture is poured into 30 ml of saturated aqueous ammonium chloride solution, the phases are separated by settling and the organic phase solvent is evaporated off under vacuum. The residue is extracted with 70 ml of diethyl ether, the organic phase is washed with 30 ml of water and this organic phase is used directly in the next step.

D) 2- (3,4-Difluorophenyl) -2-hydroxybut-3-enal, one isomer (XIX): X = F; method H, step c)

The ether solution obtained in the previous step was cooled to 5 ° C, 174 ml of 2% hydrochloric acid was added and the mixture was allowed to stir overnight at 5 ° C. The organic phase is washed with 30 ml of water, dried over magnesium sulphate and the solvent is evaporated off under vacuum. 2.67 g of the expected product is obtained.

Yield: 96% (calculated relative to the starting material of Step C of formula XVII: X = F.

E) (S) - (-) - 1- [Benzyl (2-hydroxyethyl) amino] -2- (3,4-difluorophenyl) but-3-en-2-ol (IVa): X = F, R, = - CHf / 'v I method H, step d)

1.2 ml of 2- (benzylamino) -1-ethanol are added to a solution of 1.7 g of the compound obtained in the previous step in 34 ml of acetonitrile, then 3.63 g of sodium triacetoxyborohydride and 3 drops of acetic acid, and the mixture is allowed to stir at room 1 hour. The reaction mixture is hydrolyzed by the addition of 50 ml of a 1.2 M hydrochloric acid solution, the aqueous phase is washed with 50 ml of diisopropyl ether, the aqueous phase is made alkaline by the addition of 7 ml of 10N sodium hydroxide solution and extracted with 50 ml of diisopropyl ether. The reaction mixture was concentrated in vacuo and the solvent was evaporated in vacuo. 1 g of the expected product is obtained.

Yield: 35%.

Enantiomeric purity: 99.4% (e.e. = 98.8%).

F) (S) - (-) - 4-Benzyl-2- (3,4-difluorophenyl) -2-vinylmorpholine (IIa); X = F, R 1 = -CH.

Method C

0.04 g of benzyltriethylammonium chloride is added to a solution of 1.2 g of the compound obtained in the previous step in 12 ml of toluene, and then a freshly prepared and hot solution of 2.34 g of sodium hydroxide pellets in 2.4 ml of water is added while the temperature of the medium rises to High: 32 ° C. 0.55 ml of benzenesulfonyl chloride is added at 50 ° C. After cooling to room temperature, 10 ml of water were added and the mixture was allowed to stir for 1 hour. After separation by settling, the organic phase is washed twice with 50 ml of water and dried over sodium sulphate and the solvent is evaporated off under vacuum. The residue is purified by chromatography on 60 g of silica gel eluting with cyclohexane / diethyl ether (90/10, v / v). 0.8 g of the expected product is obtained.

Yield: 70%

G) (S) - (-) - (2- [4-Benzyl-2- (3,4-difluorophenyl) morpholin-2-yl] -1-ethanol.

(IIIa): X = F, R 1 = -CH.

method A, step a) ml of a 0.5 M solution of 9-borabicyclo [3.3.1] nonane in tetrahydrofuran was added to 0.8 g of the compound prepared in the previous step under nitrogen atmosphere, the temperature of the mixture was raised to 25 ° C and is stirred for 24 hours. 6 ml of tetrahydrofuran are added, the reaction mixture is cooled to 0 ° C, 0.2 ml of a solution containing 1 ml of a 11M solution (130 volumes) of hydrogen peroxide in water and 0.64 g of sodium hydroxide pellets are added in portions five times. Stir 15 minutes at room temperature. The tetrahydrofuran is evaporated off under vacuum, the mixture is extracted with 10 ml of toluene, the organic phase is washed twice with 10 ml of water and dried over magnesium sulphate and the solvent is evaporated off under vacuum. The oil obtained is purified by chromatography on 20 g of silica gel, eluting with a dichloromethane / diethyl ether mixture (73/3, v / v). 0.78 g of the expected product is obtained.

Yield: 93%.

H) (S) - (-) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol (I): X = F; method Ά, step b)

A solution of 0.78 g of the compound obtained in the preceding step in 10 ml of methanol and 0.195 ml of concentrated hydrochloric acid was added to 0.078 g of 50% wet 10% palladium on carbon under nitrogen. The hydrogenation was carried out for 2 hours at atmospheric pressure and room temperature. The catalyst was filtered off and the filtrate was evaporated in vacuo. 0.5 g of the expected product is obtained.

Yield: 85%.

Enantiomeric purity: 99.95%.

Example 5 - Synthetic procedure V (S) - (-) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl) -1-ethanol (I): X = F

A) 2- (3,4-Difluorophenyl) -2-hydroxybut-3-enal, one isomer

This compound was prepared using the procedures described in steps A, B, C and D of Example 4.

B) 2- (3,4-Difluorophenyl) but-3-ene-1,2-diol, one isomer (XX): X = F; method I, step d)

A solution of 3.2 g of the compound obtained in the preceding step in 110 ml of toluene was cooled to 0 ° C and a solution of 0.3 g of sodium borohydride in 10 ml of ethanol was added dropwise. The reaction mixture is hydrolyzed by the addition of 100 ml of saturated ammonium chloride solution, the organic phase after separation is washed three times with 30 ml of water and dried over magnesium sulphate and the solvent is evaporated off under vacuum. The oily residue is purified by chromatography on silica gel, eluting with dichloromethane / diethyl ether (90/10, v / v). 1 g of the expected compound is obtained.

Yield: 31%.

C) 2- (3,4-Difluorophenyl) -2-vinyloxirane, one isomer (VII): X = F; method I, step e)

A solution of 1 g of the compound obtained in the preceding step and 0.04 g of benzyltriethylammonium chloride in 5 ml of dichloromethane is added at room temperature to a solution of 2 g of sodium hydroxide pellets in 2 ml of water and 0.91 g of benzenesulfonyl chloride. C. 5 ml of dichloromethane are added and the mixture is allowed to stir for 30 minutes. The reaction mixture is hydrolyzed by the addition of 20 ml of water and diluted with 20 ml of dichloromethane. After separation by settling, the organic phase is washed four times with 10 ml of water and dried over magnesium sulphate and the solvent is evaporated off under vacuum. 0.91 g of the expected product is obtained.

Yield: quantitative

D) (S) - (-) - 1- [Benzyl (2-hydroxyethyl) amino] -2- (3,4-difluorophenyl) but-3-en-2-ol (IVa): x = F, R, = - CHf method I, step f)

0.742 g of 2- (benzylamino) -1-ethanol is added to a solution of 0.894 g of the compound obtained in the preceding step in 4.5 ml of acetonitrile, and then the mixture is heated under reflux for 24 hours. The reaction mixture is evaporated in vacuo, the residue is taken up in 20 ml of toluene and the organic phase is washed three times with 10 ml of water, acidified by the addition of 20 ml of 0.5 N hydrochloric acid and extracted with 10 ml of water. The acidified aqueous phase is washed with 10 ml of toluene, made alkaline by the addition of 0.41 g of sodium hydroxide pellets and extracted with 20 ml of toluene. The organic phase is washed three times with water and dried over magnesium sulphate and the solvent is evaporated off under vacuum to give 0.99 g of the expected product.

Yield: 60%.

Enantiomeric purity: 98.8% (e.e. = 97.6%).

E) (S) - (-) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol (I): X = F; method C and then method A, steps a) and b)

The preparation is carried out in the same manner as described in steps F, G and H of Example 4, starting from the compound prepared in the previous step to give the expected product.

Example 6 - Synthetic Procedure VI (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl) -1-ethanol, L - (-) - di-para-tolyltartaric acid salt acid (I): X - F

A) 4-Benzyl-2- (3,4-difluorophenyl) -2-vinylmorpholine maleate, (IIa), (IIIa) -C ₄ H ₄ O ₄ : X'F, R 4 -CH.

This compound was prepared according to the procedures described in steps A, B, C and D of Example 1.

B) Benzyl 2- (3,4-difluorophenyl) -2-vinylmorpholine-4-carboxylate (IIb): X = F, R 1 = -COO-CH.

Method B

A mixture of 41.98 g of the compound obtained in Step A as the free base (oil) and 0.55 g of potassium carbonate is heated to 60 ° C, then 28.68 g of nitrogen are added dropwise over 25 minutes under a nitrogen atmosphere.

of benzyl chloroformate and the mixture was allowed to stir at 20 ° C for 5 hours. 100 ml of toluene and 70 ml of water are added to the still hot reaction mixture, the organic phase is separated by settling and washed with water and dried over magnesium sulphate and the solvent is evaporated off under vacuum. 64 g of the expected product are obtained, which product is used as is in the following stage.

C) Benzyl 2- (3,4-difluorophenyl) -2- (2-hydroxyethyl) morpholine-4-carboxylate (11ib): X = F, R 1 = -COO-CH ₂

method A, step a)

A solution of 6.35 g of trimethylsilyl chloride in 8 ml of tetrahydrofuran was added to a mixture of 2.21 g of sodium borohydride in 50 ml of tetrahydrofuran over 15 minutes under a nitrogen atmosphere, and the mixture was allowed to stir at room temperature for 30 minutes. prepared in the previous step, and the mixture was allowed to stir at room temperature for 1 hour, then heated at reflux for 1 hour and allowed to stir overnight at room temperature. 1.05 ml of water was carefully added dropwise to the reaction mixture, and then tetrahydrofuran was evaporated in vacuo. The residue is taken up in 60 ml of toluene, slowly added 0.24 g of tetrabutylammonium hydrogen sulphate, 5.4 ml of 10N sodium hydroxide and then 3.8 ml of 11M hydrogen peroxide in water (33%, 130 volumes, d = 1.13), the temperature of the reaction mixture being 45 ° C. After stirring for 15 minutes, 60 ml of water are added to the reaction mixture, the organic phase is separated by settling, washed twice with water (pH = 7) and dried over magnesium sulphate and the solvent is evaporated off under vacuum. 4.83 g of the expected product are obtained, which product is used as is in the following stage.

D) 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, racemic (I): X = F; method A, step b)

A solution of 0.77 g of the compound prepared in the previous step in 2.3 ml of toluene was added to 0.05 g of 50% wet 10% palladium on carbon under nitrogen. The hydrogenation was carried out at atmospheric pressure at 40 ° C for 2.5 hours. After cooling to room temperature, water was added to the mixture, and the mixture was acidified by the addition of 0.105 ml of concentrated hydrochloric acid and filtered. After settling, the acidified aqueous phase was washed with toluene, basified with 0.141 ml of 10N sodium hydroxide solution and allowed to stir for 1 hour at room temperature. The resulting precipitate was filtered, washed with water and dried under vacuum at 60 ° C. 0.17 g of the expected product is obtained.

E) (R) - (+) - 2- [2- (3,4-Difluorophenyl) morpholin-2-yl] -1-ethanol, L - (-) - di-para-tolyltartaric acid salt (I) X = F; method A, step c)

The preparation is carried out according to the procedure described in Step G of Example 1, starting from the compound prepared in the previous step to give the expected product.

Claims (31)

Claims 1. A process for preparing a compound of general pure form: formulas Even in enantiomerically wherein X is a halogen atom, its salts with inorganic or organic acids or its salts with optically active acids, characterized in that (a) a compound of formula II in racemic form, in the form of a mixture of diastereoisomers or in enantiomerically pure form: (II): (IIa): R 1 = -CH ₂ (IIb): R 1 - -COO-CH ₂ - # (Hc): R 1 = -COOCHCICH 3 (fol): R 1 = -COO-C (CH 3) 3 (He): R 1 = CH ₃ wherein X is as defined for a compound of formula I, and R 1 is a nitrogen protecting group selected from the group consisting of benzyl, benzyloxycarbonyl, 1chlorethyloxycarbonyl, tert-butyloxycarbonyl or α-methylbenzyl, converts to the compound of formula III in racemic form, in the form of a mixture of diastereoisomers or in enantiomerically pure form: 4 * 444 4 · 44 4 4 4 4 4 4 4 4 4 4 4 4 4 4 * 4444 (III): (IIIa): R 1 = (IIIb): R 1 = -COO-CH ₂ / - (IIIe): R 1 = -COOCHCICH 3 (IIId): R 1 = -COO-C (CH 3) 3 CHj b) deprotecting the compound of formula III thus obtained; c) if appropriate, when the compound of formula I thus prepared is in racemic form, the enantiomers are separated and, optionally, the enantiomerically pure compound of formula I is converted into one of its salts with inorganic or organic acids. 2. A process according to claim 1, wherein the compound of formula II in enantiomerically pure form or in racemic form is: wherein X is a halogen atom and R _x is a benzyloxycarbonyl or 1-chloroethyloxycarbonyl group, prepared by reaction of a compound of formula IIa in enantiomerically pure form or in racemic form: ·························· 4 4 Wherein 44 is the same as defined for the compound of formula II, with benzyl chloroformate or 1-chloroethyl chloroformate in the presence of a base, with or without a solvent. Process according to either of Claims 1 and 2, characterized in that the compound of the formula II in enantiomerically pure form, in the form of a mixture of diastereoisomers or in racemic form: wherein X is a halogen atom and R _x is a benzyl, tert-butyloxycarbonyl or α-methylbenzyl group, its salts with inorganic or organic acids, prepared by cyclization of the compound of formula IV in enantiomerically pure form, in the form of mixtures of diastereoisomers or in racemic form: ·· ·· • · · HO (IV), (IVa): R, = CH _2, (IVd): R = -COO-C (CH3) ₃ (IVe): R _t = CH,. wherein X and R 1 are as defined for the compound of formula II, and optionally converting the compound of formula II thus obtained into a salt. A process according to claim 3, wherein the compound of formula IV in enantiomerically pure form: wherein X is a halogen atom and R 1 is a benzyl group or an α-methylbenzyl group, its salts with inorganic or organic acids, prepare: (a) reaction of a compound of formula V in racemic form: ······ ·· · 9 9 9 9 Where X is the same as defined for the compound of formula IV and Hal is a halogen atom, with benzylamine or with R- ( +) - or S - (-) α-methylbenzylamine in the presence of a base in an inert solvent, to give the compound of formula VI in racemic form: b) separating the enantiomers or diastereoisomers of the compound of formula VI thus obtained; c) reaction of the enantiomerically pure compound of formula VI thus obtained: either with ethylene oxide in the catalytic presence of an acid in an inert solvent; or with a compound of formula Hal '' - CH 2 - CH 2 - O - R 2 XXI, wherein R ₂ is an oxygen protecting group and Hal "" is a halogen atom, in the presence of a base in an inert solvent and then removing the atom protecting group oxygen; and optionally converting the thus obtained enantiomerically pure compound of formula IV to one of its salts with inorganic or organic acids. The process according to claim 4, wherein in step a) a compound of formula V is used wherein Hal is chlorine or bromine. A process according to claim 3 wherein the compound of formula IV in racemic form or in the form of a mixture of diastereoisomers: (IV) (IVa) (IVd) (IVe) wherein X is a halogen atom and R _x is a benzyl group, a tert-butyloxycarbonyl group or an α-methylbenzyl group or one of its salts with inorganic or organic acids, prepare (a) reaction of a compound of formula V in racemic form: (V) wherein X is as defined for the compound of formula IV and Hal is a halogen atom with either 2- (benzylamino) -1-ethanol or 2-amino-1-ethanol or with (R) - or (S) -2- (α-methylbenzylamino) -1-ethanol, in the presence of a base and an inert solvent and optionally converting the thus obtained compound of formula IVa or IVe to one of its salts with inorganic or organic acids; • 4 «·· O b) if appropriate, when the compound of formula V is used in step a) with 2-amino-1-ethanol, by reacting the compound of formula IV'd thus obtained: ^X CH, I ² with di-tert-butyl dicarbonate in the presence of a base and an inert solvent to give a compound of formula IVd. A process according to claim 6, wherein the compound of formula V is used wherein Hal is chlorine or bromine. A process according to any one of claims 4 and 6, wherein the compound of formula V: II Hal where X is a halogen atom and Hal is a halogen atom, primes: a) reaction of a compound of formula VIII: X: wherein X is the same as defined for the compound of formula V, with the compound of formula IX: Hal'-CO-CH ₂ -Hal (IX) in which Hal 'and Hal is halogen, in the presence of a Lewis acid and an inert solvent to give a compound of formula X: (X) (b) reaction of the compound of formula X thus obtained with a compound of formula XI: CH ₂ = CH-Mg-Hal (XI) wherein Hal '' is a halogen atom, in an inert solvent, followed by hydrolysis to give a compound of formula IN. A process according to claim 8, wherein the compound of formula V is prepared wherein Hal is chlorine or bromine. The method of claim 8, wherein in step a) a compound of formula IX is used wherein Hal 'and Hal are each independently chlorine or bromine and in step b) a compound of formula XI is used wherein Hal is a chlorine atom or a bromine atom. The process of claim 3, wherein the compound of formula IVa in racemic form is: (IVa) wherein X is a halogen atom or one of its organic or organic acids, prepares: salts with anorgaa) reaction of a compound of formula VIII: (VHI) wherein X is as defined for a compound of formula IVa with a compound of formula IX: Hal'-CO-CH ₂ -Hal (IX) in which Hal 'and Hal is halogen, in the presence of a Lewis acid and an inert solvent to give a compound of formula X: (X) (b) reaction of the compound of formula X thus obtained with a compound of formula XII: (XII) · «f φ φ f f f f f f XII XII Wherein R ₂ is an oxygen protecting group, in the presence of a base in an inert solvent, to give a compound of formula XIII: (XIII) c) reacting the compound of formula XIII thus obtained with a compound of formula XI: CH ₂ = CH-Mg-Hal '' (XI) where Hal '' is a halogen atom, in an inert solvent, followed by hydrolysis of XIV: to form a compound of formula (XIV) from a compound of formula XIV and d) removing the protecting group, optionally by converting the thus obtained compound of formula IVa to one of its salts with inorganic or organic acids. A process according to claim 11, wherein in step a) a compound of formula IX is used, wherein Hal and Hal 'are each independently chlorine or bromine, in step b) a compound of formula XII is used, wherein R is ₂ is a tetrahydropyran-2-yl group and in step c) a compound of formula XI is used wherein Hal '' is chlorine or bromine. ··················· 13. The method of claim 3, wherein the compound of formula IVa in enantiomerically pure form: Where X is a halogen atom or one of its salts with inorganic or organic acids, it prepares: a) reaction of a compound of formula XV: <(XV) wherein X is as defined for the compound of formula IVa and Hal is a halogen atom, with methyl (R) - or (S) -2-phenylhexahydropyrrolo [1,2-c] imidazole-3-carboxylate of formula XVI : CH ₃ (XVI) in the presence of magnesium chloride in an inert solvent, followed by hydrolysis to give the compound of formula XVII in enantiomerically pure form: of formula XI (XVII) CH ₂ = CH-Mg-Hal (XI) wherein Hal is a halogen atom, in an inert solvent, followed by hydrolysis to give the compound of formula XVIII in enantiomerically pure form: (XVIH) c) hydrolyzing the compound of formula XVIII thus obtained by treatment with an acid in an inert solvent mixed with water to give the compound of formula XIX in enantiomerically pure form: (XIX) d) reacting the compound of formula XIX thus obtained with 2- (benzylamino) -1-ethanol in the presence of an acid in an inert solvent, then reducing the imine salt formed as an intermediate with a reducing agent and optionally converting the enantiomerically pure compound of formula IVa to one of its inorganic salts or organic acids. The process of claim 3, wherein the compound of formula IVa in enantiomerically pure form: (IVa) wherein X is a halogen atom or one of its salts with inorganic or organic acids, prepares: a) reaction of a compound of formula XV: wherein X is as defined for the compound of formula IVa and Hal '' is halogen, with methyl (R) - or (S) -2-phenylhexahydropyrrolo [1,2-c] imidazole-3-carboxylate of formula XVI: (XVI) in the presence of magnesium chloride in an inert solvent, followed by hydrolysis to give the compound of formula XVII in enantiomerically pure form: (XVII) (b) reaction of the compound of formula XVII thus obtained with a compound of formula XI: CH ₂ = CH-Mg-Hal '' (XI) where Hal '' is a halogen atom, in an inert solvent, followed by hydrolysis to give the compound of formula XVIII in enantiomerically pure form: (XVIII) c) hydrolyzing the compound of formula XVIII thus obtained by treatment with an acid in an inert solvent as a mixture with water to obtain the compound of formula XIX in enantiomerically pure form: (XIX) x • »· · · · d) reducing the compound of formula XIX thus obtained with a reducing agent in an inert solvent to obtain a compound of formula XX: e) cyclizing the compound of formula XX thus obtained to obtain a compound of formula VII in enantiomerically pure form: f) reacting the compound of formula VII thus obtained with 2- (benzylamino) -1-ethanol in the presence of a base and an inert solvent and optionally converting the thus obtained enantiomerically pure compound of formula IVa to one of its salts with inorganic or organic acids. Process according to any one of claims 13 and 14, characterized in that in step a) a compound of formula XV is used, wherein Hal '' is a chlorine or bromine atom, and in step b) a compound of formula XI is used, wherein Hal is a chlorine atom or a bromine atom. Process according to any one of claims 1, 2, 3, 4, 6, 8, 11, 13 and 14, characterized in that compounds of formula I, IIa, IIb, IIc, IIc, Ile, IVa, IVd, IVe or V, wherein X is chlorine or bromine. * · Φ ·· · 94 9 99 99 • · · * 9 99 9 9 · · • · · 9 9 9 • · 9 99 9 ·· ··· 99 9999 17. Enantiomerically pure compound of formula I: wherein X is a halogen atom, in the form of an optically active salt with an optically active acid. A compound according to claim 17 in the form of a salt with L - (-) - or D (+) - di-paratolyltartaric acid. 19. Compound of Formula II: fc (H): (IIIa): R 1 = (IIb): R 1 = -COO-CH ₂ - (R 1) (Hc): R 1 = -COOCHCl 3 (id): R 1 = -COO-C ( CH ₃ ) ₃ (Ile): R, -C -C CH wherein X is halogen and R 1 is a nitrogen protecting group selected from the group consisting of benzyl, benzyloxycarbonyl, 1-chloroethyloxycarbonyl, tert-butyloxycarbonyl or α-methylbenzyl, in racemic form, in enantiomerically pure form or in the form of mixtures of diastereoisomers and possible salts thereof with inorganic or organic acids. 20. Compound of Formula IV: (IV): (IVa): R 1 = -CH (IVd): R 1 = -COO-C (CH ₃ ) ₃ (IVe): R 1 CH wherein X is halogen and R 1 is benzyl, tert-butyloxycarbonyl or α-methylbenzyl in racemic form, in enantiomerically pure form or in the form of a mixture of diastereoisomers and its possible salts with inorganic or organic acids. 21. A compound of formula V: wherein X is a halogen atom and Hal is a halogen atom. A compound according to claim 21, wherein Hal is chlorine or bromine. 23. A compound of formula VI: (VI): (VIe) wherein X is a halogen atom and R 1 is a benzyl or amethylbenzyl group, in racemic form, in enantiomerically pure form, or in the form of a mixture of diastereoisomers and a salt thereof with inorganic or organic acids or optically active acids . 83 An enantiomerically pure compound of formula VIa according to claim 23 in the form of a salt with L - (+) - or D - (-) - mandelic acid. 25. Compound of formula (VII): (V ') wherein X is a halogen atom, in racemic form or in enantiomerically pure form. 26. Compound of formula (XIII): <3r (XHI) wherein X is halogen and R ₂ is a protecting group, oxygen atom, and salts thereof with inorganic or organic acids. 27. A compound of formula XIV: • t 99 99 9 9 9 9 9 9 9 9 (XIV) where X is a halogen atom and R ₂ is an oxygen protecting group and its salts with inorganic or organic acids. A compound according to claim 26 or 27 of formula XIII or XIV, wherein R ₂ is tetrahydropyran-2-yl. 29. Compound of Formula XIX: (XIX) in.· Where X is a halogen atom, in racemic form or in enantiomerically pure form. 30. Compound of Formula XX: (XX) wherein X is a halogen atom, in racemic form or in enantiomerically pure form. A compound according to any one of claims 17 to 30 of formula I, II, IV, V, VI, VII, XIII, XIV, XIX or XX, wherein X is chlorine or fluorine.